1. Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity.
期刊:Science (New York, N.Y.)
日期:2025-04-25
DOI :10.1126/science.adr3026
Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
添加收藏
创建看单
引用
1区Q1影响因子: 9.1
英汉
2. Molecular Imaging in Cancer Chemoresistance: What's Brewing?
期刊:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
日期:2025-03-03
DOI :10.2967/jnumed.124.268967
Cancer therapy has advanced with molecularly targeted approaches and immunotherapy, yet chemotherapy remains essential for many aggressive cancers, including breast, lung, ovarian, pancreatic, bladder, sarcoma, and lymphomas. A major challenge is chemoresistance, in which cancer cells evade chemotherapy's cytotoxic effects. Overexpression of adenosine triphosphate-binding cassette transporters, especially P-glycoprotein, significantly contributes to this resistance. Thus, imaging biomarkers are urgently needed to detect P-glycoprotein overexpression in vivo, identify resistant cancer cell clones, and map their distribution and heterogeneity within tumors. This article reviews the applications of SPECT, PET, and optical imaging in addressing chemoresistance. It emphasizes the potential of these modalities to enhance cancer treatment by enabling early identification of resistant clones and improving therapeutic strategies. The article outlines key steps required for the integration of molecular imaging into clinical practice, aiming to overcome chemoresistance and optimize patient outcomes.
Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 25.3
英汉
4. Clinical Implications of Basic Research: Exploring the Transformative Potential of Spatial 'Omics in Uro-oncology.
期刊:European urology
日期:2024-09-02
DOI :10.1016/j.eururo.2024.08.025
New spatial molecular technologies are poised to transform our understanding and treatment of urological cancers. By mapping the spatial molecular architecture of tumours, these platforms uncover the complex heterogeneity within and around individual malignancies, offering novel insights into disease development, progression, diagnosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-cell interactions in the tumour microenvironment. A whole transcriptome/genome/proteome-level spatial analysis is hypothesis generating, particularly in the areas of risk stratification and precision medicine. Current challenges include reagent costs, harmonisation of protocols, and computational demands. Nonetheless, the evolving landscape of the technology and evolving machine learning applications have the potential to overcome these barriers, pushing towards a future of personalised cancer therapy, leveraging detailed spatial cellular and molecular data. PATIENT SUMMARY: Tumours are complex and contain many different components. Although we have been able to observe some of these differences visually under the microscope, until recently, we have not been able to observe the genetic changes that underpin cancer development. Scientists are now able to explore molecular/genetic differences using approaches such as "spatial transcriptomics" and "spatial proteomics", which allow them to see genetic and cellular variation across a region of normal and cancerous tissue without destroying the tissue architecture. Currently, these technologies are limited by high associated costs, and a need for powerful and complex computational analysis workflows. Future advancements and results through these new technologies may assist patients and their doctors as they make decisions about treating their cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 25.7
英汉
5. ERBB2 Comprehensive Profiling and Prognostication in Stage III Colon Cancer: Findings From PETACC8 and IDEA-France Cohorts.
期刊:Gastroenterology
日期:2024-11-28
DOI :10.1053/j.gastro.2024.10.046
BACKGROUND & AIMS:ERBB2 pathway activation, through amplification or activating mutations, represents a new target for colon cancer (CC) treatment. Molecular methods were compared with the gold standard for assessing ERBB2 status, and the prognostic value of ERBB2 amplification, mutations, and expression was determined using data from 2 phase 3 trials involving nearly 3000 patients with stage III CC. METHODS:In the PETACC8 trial, immunohistochemistry and fluorescence in situ hybridization, DNA, and RNA analysis were performed on 1813, 1719, and 1733 samples, respectively. In the IDEA-France trial, DNA and RNA sequencing was performed on 1129 and 1263 samples. The breast cancer SCAN-B cohort (N = 3409) served as an external reference. A new molecular ERBB2-amplified status was defined using ERBB2 next-generation sequencing score, RNA sequencing expression, and clustering based on ERBB2 neighboring gene expression. Concordance between diagnostic techniques and the association between time to recurrence (TTR) and ERBB2-status were evaluated. RESULTS:The prevalence of the molecular ERBB2-amplified group was 1.85% in PETACC8 and 1.5% in IDEA-France, with a concordance of 0.81 (95% CI, 0.70-0.92) with the gold standard immunohistochemistry and fluorescence in situ hybridization method in PETACC8. A nonlinear relationship was observed between TTR and ERBB2 expression, with extreme groups showing a less favorable prognosis (P < .0001) in both colon and breast cancers. Patients with molecular ERBB2-amplified status or mutations had the poorest prognosis, followed by low-expression and intermediate-expression groups (3-year TTR of 67.0%, 71.2%, and 77.9%, respectively). In multivariate analysis, the low-expression group had a significantly shorter TTR (hazard ratio, 1.28; 95% CI, 1.07-1.52). CONCLUSIONS:The molecular definition of ERBB2 status could represent a cost-effective alternative in stage III CC. ERBB2 alterations and low RNA expression significantly reduced TTR, highlighting the complex role of ERBB2.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
打开PDF
登录
英汉
6. Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
期刊:Cancer cell
日期:2025-03-20
DOI :10.1016/j.ccell.2025.03.002
Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
7. Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
期刊:Nature immunology
日期:2025-04-22
DOI :10.1038/s41590-025-02134-6
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.
添加收藏
创建看单
引用
1区Q1影响因子: 44.7
跳转PDF
登录
英汉
8. Vitamin D regulates microbiome-dependent cancer immunity.
期刊:Science (New York, N.Y.)
日期:2024-04-25
DOI :10.1126/science.adh7954
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
添加收藏
创建看单
引用
1区Q1影响因子: 9.4
英汉
9. Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
期刊:Proceedings of the National Academy of Sciences of the United States of America
日期:2024-12-03
DOI :10.1073/pnas.2412157121
Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.
添加收藏
创建看单
引用
2区Q1影响因子: 16.6
跳转PDF
登录
英汉
10. ScDrugAct: a comprehensive database to dissect tumor microenvironment cell heterogeneity contributing to drug action and resistance across human cancers.
期刊:Nucleic acids research
日期:2025-01-06
DOI :10.1093/nar/gkae994
The transcriptional heterogeneity of tumor microenvironment (TME) cells is a crucial factor driving the diversity of cellular response to drug treatment and resistance. Therefore, characterizing the cells associated with drug treatment and resistance will help us understand therapeutic mechanisms, discover new therapeutic targets and facilitate precision medicine. Here, we describe a database, scDrugAct (http://bio-bigdata.hrbmu.edu.cn/scDrugAct/), which aims to establish connections among drugs, genes and cells and dissect the impact of TME cellular heterogeneity on drug action and resistance at single-cell resolution. ScDrugAct is curated with drug-cell connections between 3838 223 cells across 34 cancer types and 13 857 drugs and identifies 17 274 drug perturbation/resistance-related genes and 276 559 associations between >10 000 drugs and 53 cell types. ScDrugAct also provides multiple flexible tools to retrieve and analyze connections among drugs, genes and cells; the distribution and developmental trajectories of drug-associated cells within the TME; functional features affecting the heterogeneity of cellular responses to drug perturbation and drug resistance; the cell-specific drug-related gene network; and drug-drug similarities. ScDrugAct serves as an important resource for investigating the impact of the cellular heterogeneity of the TME on drug therapies and can help researchers understand the mechanisms of action and resistance of drugs, as well as discover therapeutic targets.
添加收藏
创建看单
引用
2区Q2影响因子: 5.1
跳转PDF
登录
英汉
11. Emerging Treatments Targeting the Tumor Microenvironment for Advanced Chondrosarcoma.
期刊:Cells
日期:2024-06-04
DOI :10.3390/cells13110977
Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
12. Whole Lung Irradiation in Rhabdomyosarcoma With Lung Metastases: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2024-09-10
DOI :10.1200/JCO.24.00928
PURPOSE:Patients with rhabdomyosarcoma with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases. METHODS:Patients with rhabdomyosarcoma with lung metastases enrolled on four Children's Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free survival (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI. RESULTS:In 143 patients with rhabdomyosarcoma with lung metastases, 65 patients (45.5%) received WLI and 78 patients (54.5%) did not receive WLI despite protocol requirements. The 5-year EFS was 38.3% (95% CI, 24.8 to 51.8) in patients who received WLI and 25.2% (95% CI, 13.8 to 36.6) in patients who did not receive WLI ( = .0496). The 5-year OS was 45.5% (95% CI, 31.8 to 59.3) in patients who received WLI and 32.4% (95% CI, 20.4 to 44.4) in patients who did not receive WLI ( = .08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariable analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score. CONCLUSION:WLI is associated with improved EFS in patients with rhabdomyosarcoma with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.
添加收藏
创建看单
引用
2区Q1影响因子: 7.1
跳转PDF
登录
英汉
13. Fused in sarcoma regulates glutamate signaling and oxidative stress response.
期刊:Free radical biology & medicine
日期:2023-11-23
DOI :10.1016/j.freeradbiomed.2023.11.015
Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor GLR-1. We found that fust-1 ALS mutations act as loss-of-function in SOD-1 and VGLUT/EAT-4 phenotypes, whereas the fust-1 ALS mutations act as gain-of-function in redox homeostasis and the microbe-induced oxidative stress response. We hypothesized that FUST-1 is a link between glutamate signaling and SOD-1. Our results may provide new insights into the human ALS alleles and their roles in pathological mechanisms that lead to ALS.
添加收藏
创建看单
引用
1区Q1影响因子: 22.5
跳转PDF
登录
英汉
14. Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.
期刊:JAMA oncology
日期:2023-12-01
DOI :10.1001/jamaoncol.2023.4015
Importance:Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective:To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants:This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions:Two doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures:Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results:Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance:In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT02180698.
添加收藏
创建看单
引用
2区Q1影响因子: 5.7
跳转PDF
登录
英汉
15. The outcomes and treatment strategies in metastatic soft tissue sarcoma treated with immunotherapy-based therapy: a three-center study.
期刊:Frontiers in immunology
日期:2025-03-28
DOI :10.3389/fimmu.2025.1504117
Background:Preclinical studies showed that cytotoxic agents and antiangiogenic agents had regulatory effects in the tumor immune microenvironment of soft tissue sarcoma (STS), and then enhance the antitumor effect of immunotherapy. This study was to investigate the efficacy and safety of immunotherapy-based therapy in metastatic STS. Methods:We conducted a retrospective analysis in three centers where some patients received immunotherapy-based therapy consisting of immunotherapy alone or in combination with systemic agents (cytotoxic agents and/or antiangiogenic agents). The primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS), and Kaplan-Meier method was used to compare survival. Results:A total of 79 patients were included in this study. With the median follow-up of 14.2 months, the mPFS and mOS was 7.5 months and 19.5 months, respectively. The PFS (P < 0.01) and OS (P < 0.01) were significantly better in the alveolar soft part sarcoma (ASPS) group compared to the non-ASPS group. Patients who treated in ≤2 lines had longer PFS (P < 0.01) and OS (P < 0.01) compared to those in subsequent lines. Further analysis was performed according to histopathological types, in patients with ASPS, the combination of immunotherapy-based therapy resulted in a longer PFS (P < 0.01) compared to immunotherapy in monotherapy. Similarly, the patients treated in ≤2 lines had longer PFS (P=0.03) and OS (P < 0.01) compared to in subsequent lines. In patients with non-ASPS, patients with potentially sensitive sarcomas (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, myxofibrosarcoma, and angiosarcoma) had a longer PFS (P = 0.02) and OS (P = 0.03) compared to other subtypes. The OS (P = 0.03) for patients with potentially sensitive sarcomas treated in ≤2 lines showed a long trend compared to subsequent lines. Most adverse events reported were mild and tolerable. Conclusions:The immunotherapy-based therapy showed promising activity in survival, especially in certain histological subtypes (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, myxofibrosarcoma, and angiosarcoma), as well as in combination treatment and in early lines. Prospective researches are needed to confirm the potential benefits.
添加收藏
创建看单
引用
1区Q1影响因子: 40.8
打开PDF
登录
英汉
16. Breast cancer: pathogenesis and treatments.
期刊:Signal transduction and targeted therapy
日期:2025-02-19
DOI :10.1038/s41392-024-02108-4
Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
英汉
17. Diet-microbiome interactions in cancer.
期刊:Cancer cell
日期:2025-04-03
DOI :10.1016/j.ccell.2025.03.013
Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
跳转PDF
登录
英汉
18. Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2025-01-13
DOI :10.1200/JCO-24-02081
Colorectal cancer (CRC) remains a major global health burden, being one of the most prevalent cancers with high mortality rates. Despite advances in conventional treatment modalities, patients with metastatic CRC often face limited options and poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy, initially successful in hematologic malignancies, presents a promising avenue for treating solid tumors, including CRC. This review explores the potential of CAR-T cell therapy in CRC by analyzing clinical trials and highlighting prominent CRC-specific targets. We discuss the challenges such as immunosuppressive microenvironment, tumor heterogeneity, and physical barriers that limit CAR-T efficacy. Emerging strategies, such as logic-gated and dual-targeting CAR-T cells, offer practical solutions to overcome these hurdles. Furthermore, we explore the combination of CAR-T cell therapy with immune checkpoint inhibitors to enhance T-cell persistence and tumor infiltration. As the field continues to evolve, CAR-T cell therapies hold significant potential for revolutionizing the treatment landscape of CRC.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
英汉
19. Midkine links aging with breast cancer-A new predictor of cancer risk.
期刊:Cancer cell
日期:2024-10-03
DOI :10.1016/j.ccell.2024.09.003
Despite aging being one of the strongest risk factors for cancer, little is known about the biological mechanisms that promote tumor initiation. In this issue of Cancer Cell, Yan et al. address this fundamental question in the context of breast cancer and report that midkine is upregulated during the aging process and can promote tumorigenesis.
添加收藏
创建看单
引用
1区Q1影响因子: 23
英汉
20. Aspirin is associated with lower risk of pancreatic cancer and cancer-related mortality in patients with diabetes mellitus.
期刊:Gut
日期:2025-03-06
DOI :10.1136/gutjnl-2024-333329
BACKGROUND:Patients with type 2 diabetes mellitus (T2DM) have higher pancreatic cancer (PC) risk. While aspirin has chemopreventive effects on digestive cancers, its effect on PC among patients with T2DM is unclear. METHODS:This retrospective cohort study identified newly diagnosed adult patients with T2DM in Hong Kong between 2001 and 2015 from a territory-wide healthcare registry. Exclusion criteria were history of PC, pancreatic cyst, IgG4 disease, or pancreatectomy. To address reverse causality between PC and T2DM, we excluded patients with PC diagnosed within 1 year of T2DM. We also excluded patients with less than 1 year of observation. Primary outcome was PC, and secondary outcomes were PC-related and all-cause mortality. Aspirin use was treated as time-varying variable (≥180 day-use/year) to address immortal-time bias, and multivariable Cox regression model was employed to derive adjusted HR (aHR). Propensity-score (PS) matching was used as secondary analysis. RESULTS:Among 343 966 newly diagnosed patients with T2DM (median follow-up: 10.5 years; IQR: 7.7-14.5 years), 1224 (0.36%) developed PC. There were 51 151 (14.9%) deaths from any cause, and 787 (0.2%) died from PC. Aspirin use was associated with lower PC risk in both time-dependent (aHR: 0.58; 95% CI 0.49 to 0.69) and PS matching analysis (aHR: 0.61; 95% CI 0.48 to 0.77). An inverse relationship was observed with increasing dose and duration of aspirin use ( <0.001). Aspirin was also associated with a lower risk of PC-related mortality (aHR: 0.43; 95% CI 0.34 to 0.53) and all-cause mortality (aHR: 0.78; 95% CI 0.76 to 0.80). CONCLUSION:Aspirin use may be an oncopreventive strategy to reduce PC risk in patients with T2DM. Further studies are warranted to validate the study findings.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
21. Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.
期刊:Molecular cancer
日期:2024-10-31
DOI :10.1186/s12943-024-02114-8
BACKGROUND:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS:To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS:Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS:Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
22. Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer.
期刊:Molecular cancer
日期:2024-10-30
DOI :10.1186/s12943-024-02164-y
Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
英汉
23. Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain.
期刊:Cancer cell
日期:2024-09-12
DOI :10.1016/j.ccell.2024.08.015
Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.
添加收藏
创建看单
引用
2区Q1影响因子: 6.4
英汉
24. Role of F-FDG-PET/CT in the initial staging of very high-risk Ewing Sarcoma in a prospective multicentric Phase II Study: Is there still a place for bone marrow sampling?
期刊:British journal of cancer
日期:2024-10-08
DOI :10.1038/s41416-024-02864-8
BACKGROUND:The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. METHODS:In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. RESULTS:Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. DISCUSSION:These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.
添加收藏
创建看单
引用
1区Q1影响因子: 29.7
跳转PDF
登录
英汉
25. MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer.
期刊:Cancer discovery
日期:2024-12-02
DOI :10.1158/2159-8290.CD-23-1529
The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from Helicobacter pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression. Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas. See related commentary by Gauthier-Coles and Sheltzer, p. 2312.
添加收藏
创建看单
引用
1区Q1影响因子: 72.5
英汉
26. Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
期刊:Nature reviews. Cancer
日期:2024-10-10
DOI :10.1038/s41568-024-00752-0
From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.
添加收藏
创建看单
引用
1区Q1影响因子: 51.4
英汉
27. Chemical Design of Magnetic Nanomaterials for Imaging and Ferroptosis-Based Cancer Therapy.
期刊:Chemical reviews
日期:2025-02-14
DOI :10.1021/acs.chemrev.4c00546
Ferroptosis, an iron-dependent form of regulatory cell death, has garnered significant interest as a therapeutic target in cancer treatment due to its distinct characteristics, including lipid peroxide generation and redox imbalance. However, its clinical application in oncology is currently limited by issues such as suboptimal efficacy and potential off-target effects. The advent of nanotechnology has provided a new way for overcoming these challenges through the development of activatable magnetic nanoparticles (MNPs). These innovative MNPs are designed to improve the specificity and efficacy of ferroptosis induction. This Review delves into the chemical and biological principles guiding the design of MNPs for ferroptosis-based cancer therapies and imaging-guided therapies. It discusses the regulatory mechanisms and biological attributes of ferroptosis, the chemical composition of MNPs, their mechanism of action as ferroptosis inducers, and their integration with advanced imaging techniques for therapeutic monitoring. Additionally, we examine the convergence of ferroptosis with other therapeutic strategies, including chemodynamic therapy, photothermal therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy, within the context of nanomedicine strategies utilizing MNPs. This Review highlights the potential of these multifunctional MNPs to surpass the limitations of conventional treatments, envisioning a future of drug-resistance-free, precision diagnostics and ferroptosis-based therapies for treating recalcitrant cancers.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
28. Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient cancers.
期刊:Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
日期:2024-10-17
DOI :10.1016/j.drup.2024.101160
Immunotherapy has revolutionized cancer treatment, yet the efficacy of immunotherapeutic approaches remains limited. Resistance to ferroptosis is one of the reasons for the poor therapeutic outcomes in tumors with Kelch-like ECH-associated protein 1 (KEAP1) mutations. However, the specific mechanisms by which KEAP1-mutant tumors resist immunotherapy are not fully understood. In this study, we showed that the loss of function in KEAP1 results in resistance to ferroptosis. We identified NAD(P)H Quinone Dehydrogenase 1 (NQO1) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and revealed that inducing NQO1-mediated ferroptosis in KEAP1-deficient tumors triggers an antitumor immune cascade. Additionally, it was found that NQO1 protein levels could serve as a candidate biomarker for predicting sensitivity to immunotherapy in clinical tumor patients. We validated these findings in several preclinical tumor models. Overall, KEAP1 mutations define a unique disease phenotype, and targeting its key downstream molecule NQO1 offers new hope for patients with resistance to immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 40.8
跳转PDF
登录
英汉
29. Intranasal prime-boost RNA vaccination elicits potent T cell response for lung cancer therapy.
期刊:Signal transduction and targeted therapy
日期:2025-03-24
DOI :10.1038/s41392-025-02191-1
The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy. Although many cancers originate in mucosal tissues, current RNA cancer vaccines are mainly administered non-mucosally. Here, we developed a non-invasive intranasal cancer vaccine utilizing circular RNA encapsulated in lipid nanoparticles to induce localized mucosal immune responses. This strategy elicited potent anti-tumor T cell responses in preclinical lung cancer models while mitigating the systemic adverse effects commonly associated with intravenous RNA vaccination. Specifically, type 1 conventional dendritic cells were indispensable for T cell priming post-vaccination, with both alveolar macrophages and type 1 conventional dendritic cells boosting antigen-specific T cell responses in lung tissues. Moreover, the vaccination facilitated the expansion of both endogenous and adoptive transferred antigen-specific T cells, resulting in robust anti-tumor efficacy. Single-cell RNA sequencing revealed that the vaccination reprograms endogenous T cells, enhancing their cytotoxicity and inducing a memory-like phenotype. Additionally, the intranasal vaccine can modulate the response of CAR-T cells to augment therapeutic efficacy against tumor cells expressing specific tumor-associated antigens. Collectively, the intranasal RNA vaccine strategy represents a novel and promising approach for developing RNA vaccines targeting mucosal malignancies.
添加收藏
创建看单
引用
1区Q1影响因子: 20.1
跳转PDF
登录
英汉
30. Copper in cancer: friend or foe? Metabolism, dysregulation, and therapeutic opportunities.
期刊:Cancer communications (London, England)
日期:2025-02-13
DOI :10.1002/cac2.70005
Copper, one of the essential nutrients for the human body, acts as an electron relay in multiple pathways due to its redox properties. Both deficiencies and excesses of copper lead to cellular fragility. Therefore, it can manifest pro- and anti-cancer properties in tumors. Therefore, it is crucial to clarify the copper activity within the cell. We have thoughtfully summarized the metabolic activities of copper from a macro and micro perspective. Cuproptosis, as well as other forms of cell death, is directly or indirectly interfered with by Cu, causing cancer cell death. Meanwhile, we did pan-cancer analysis of cuproptosis-related genes to further clarify the roles of these genes. In addition, copper has been found to be involved in multiple pathways within the metastasis of cancer cells. Given the complexity of copper's role, we are compelled to ask: is copper a friend or a foe? Up to now, copper has been used in various clinical applications, including protocols for measurement of copper concentration and bioimaging of radioactive Cu. But therapeutically it is still a continuation of the old medicine, and new possibilities need to be explored, such as the use of nanomaterials. Some studies have also shown that copper has considerable interventional power in metabolic cancers, which provides the great applications potential of copper therapy in specific cancer types. This paper reviews the dual roles played by cuproptosis in cancer from the new perspectives of oxidative stress, cell death, and tumor metastasis, and points out the value of its application in specific cancer types, summarizes the value of its testing and imaging from the perspective of clinical application as well as the current feasible options for the new use of the old drugs, and emphasizes the prospects for the application of nano-copper.
添加收藏
创建看单
引用
1区Q1影响因子: 16.1
跳转PDF
登录
英汉
31. Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells.
期刊:Angewandte Chemie (International ed. in English)
日期:2024-11-18
DOI :10.1002/anie.202412477
Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu homeostasis in cancer cells are rarely explored because small molecule Cu chelators have poor binding affinity in comparison to the intracellular Cu chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu chaperone-inspired supramolecular approach to disrupt Cu homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu binding must work in synergy to successfully disrupt Cu homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
打开PDF
登录
英汉
32. SOX17 enables immune evasion of early colorectal adenomas and cancers.
期刊:Nature
日期:2024-02-28
DOI :10.1038/s41586-024-07135-3
A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, Kras and Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8 T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5 tumour cells to produce immune-evasive LGR5 tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression.
添加收藏
创建看单
引用
1区Q1影响因子: 40.8
跳转PDF
登录
英汉
33. AXL signaling in cancer: from molecular insights to targeted therapies.
期刊:Signal transduction and targeted therapy
日期:2025-02-10
DOI :10.1038/s41392-024-02121-7
AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL in mediating these tumor-promoting pathways. We discuss a range of therapeutic strategies, including recently developed small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs), anti-AXL-CAR, and combination therapies. These interventions are being examined in both preclinical and clinical studies, offering the potential for improved drug sensitivity and therapeutic efficacy. We further discuss the mechanisms of acquired therapeutic resistance, particularly the crosstalk between AXL and other critical receptor tyrosine kinases (RTKs) such as c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, and FLT3. Finally, we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.
添加收藏
创建看单
引用
1区Q1影响因子: 29.5
打开PDF
登录
英汉
34. Disruption of the sorcin‒PAX5 protein‒protein interaction induces ferroptosis by promoting the FBXL12-mediated ubiquitination of ALDH1A1 in pancreatic cancer.
期刊:Journal of hematology & oncology
日期:2025-03-07
DOI :10.1186/s13045-025-01680-8
BACKGROUND:Pancreatic cancer is one of the most malignant cancers, and limited therapeutic options are available. The induction of ferroptosis is considered to be a novel, promising strategy that has potential in cancer treatment, and ferroptosis inducers may be new options for eradicating malignant cancers that are resistant to traditional drugs. The exact mechanism underlying the function of sorcin in the initiation and progression of pancreatic cancer remains unclear. METHODS:The expression of sorcin in cancer tissues was assessed by analyzing TCGA, GEO and immunohistochemical staining data, and the function of sorcin in the induction of ferroptosis in pancreatic cancer cells was investigated. The mechanism underlying the function of sorcin was revealed through proteomics, co-IP, Ch-IP, and luciferase assays. Natural product screening was subsequently performed to screen for products that interact with sorcin to identify new ferroptosis inducers. RESULTS:We first showed that sorcin expression was positively correlated with the survival and tumor stages of patients with pancreatic cancer, and we revealed that sorcin inhibited ferroptosis through its noncalcium binding function. Furthermore, we discovered that sorcin interacted with PAX5 in the cytoplasm and inhibited PAX5 nuclear translocation, which in turn decreased FBXL12 protein expression and then reduced ALDH1A1 ubiquitination, thus inhibiting ferroptosis. Moreover, an in-house natural product screen revealed that celastrol inhibited the interaction of sorcin and PAX5 by directly binding to the Cys194 residue of the sorcin protein; disruption of the sorcin-PAX5 interaction promoted the nuclear translocation of PAX5, induced the expression of FBXL12, increased the ubiquitylation of ALDH1A1, and eventually induced ferroptosis in pancreatic cancer cells. CONCLUSION:In this study, we revealed the mechanism of action of sorcin, which is a druggable target for inducing ferroptosis, we identified celastrol as a novel agent that induces ferroptosis, and we showed that disrupting the sorcin-PAX5 interaction is a promising therapeutic strategy for treating pancreatic cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 14.7
跳转PDF
登录
英汉
35. Lactylation of METTL16 promotes cuproptosis via mA-modification on FDX1 mRNA in gastric cancer.
期刊:Nature communications
日期:2023-10-20
DOI :10.1038/s41467-023-42025-8
Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the mA modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore- elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.
添加收藏
创建看单
引用
1区Q1影响因子: 10.7
英汉
36. Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma.
期刊:Developmental cell
日期:2025-03-20
DOI :10.1016/j.devcel.2025.02.016
BRAF mutant melanomas treated with BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) almost invariably develop drug resistance, accompanied by restored glucose metabolism. How resumed glycolysis controls acquired resistance remains unknown. Here, we identify that lysine-specific demethylase 1 (LSD1) lactylation, induced by re-accumulated lactate in both human and murine BRAFi/MEKi-resistant melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with Fos-related antigen 1 (FosL1), preventing its degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21) and selectively enhancing its genomic enrichment. We further demonstrate that lactylated LSD1 co-directs gene transcription with FosL1 to repress ferroptosis via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibition activates ferroptosis, resulting in drastic regression of drug-resistant murine melanoma when combined with immunotherapy. Our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in BRAFi/MEKi-resistant melanoma, providing a therapeutically actionable strategy to overcome resistance to targeted therapy and immunotherapy.
添加收藏
创建看单
引用
2区Q1影响因子: 4.4
英汉
37. The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer.
期刊:FASEB journal : official publication of the Federation of American Societies for Experimental Biology
日期:2025-01-15
DOI :10.1096/fj.202402139R
Lung cancer progression is characterized by intricate epigenetic changes that impact critical metabolic processes and cell death pathways. In this study, we investigate the role of histone lactylation at the AIM2 locus and its downstream effects on ferroptosis regulation and lung cancer progression. We utilized a combination of biochemical assays, including chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and western blotting to assess histone lactylation levels and gene expression. To evaluate the functional consequences, we employed gain- and loss-of-function approaches using shikonin treatment and siRNA knockdowns in lung cancer cell lines. Additionally, we assessed the impact of these interventions on ferroptosis markers and lung cancer cell viability. Our results reveal that increased histone lactylation at the AIM2 locus correlates with enhanced transcriptional activity of AIM2, leading to reduced ferroptosis through modulation of ACSL4 and STAT5B. Furthermore, we demonstrate that shikonin, a natural naphthoquinone derivative, effectively downregulates PKM2 and AIM2 expression, thereby inhibiting lung cancer progression by counteracting the effects of histone lactylation on AIM2 expression. These findings highlight the importance of histone lactylation in regulating AIM2 expression and ferroptosis in lung cancer cells. They also suggest that targeting PKM2 and AIM2, particularly through the use of shikonin, could be a promising strategy for developing novel therapies against lung cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 8.1
跳转PDF
登录
英汉
38. Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.
期刊:Cell death & disease
日期:2025-03-20
DOI :10.1038/s41419-025-07498-z
Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is a post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate that histone lactylation enhances CCSC chemoresistance both in vitro and in vivo. Furthermore, our findings showed that p300 catalyzes the lactylation of histone H4 at K12, whereas HDAC1 facilitates its delactylation in CCSCs. Notably, lactylation at H4K12 (H4K12la) upregulates GCLC expression and inhibits ferroptosis in CCSCs, and the inhibition of p300 or LDHA decreases H4K12la levels, thereby increasing the chemosensitivity of CCSCs. Additionally, the GCLC inhibitor BSO promotes ferroptosis and sensitizes CCSCs to oxaliplatin. Taken together, these findings suggest that histone lactylation upregulates GCLC to inhibit ferroptosis signaling, thus enhancing CCSC chemoresistance. These findings provide new insights into the relationship between cellular metabolism and chemoresistance and suggest potential therapeutic strategies targeting p300, LDHA, and GCLC. We showed that histones H4K12 lactylation promoted chemoresistance in CSCs. p300 catalyzes the lactylation of histone H4 at K12, HDAC1 inhibits the histone lactylation at the same site. H4K12la in CSCs regulates the expression of the ferroptosis-related gene GCLC, thereby inhibiting ferroptosis and leading to chemoresistance. Targeting the p300, LDHA, or GCLC may be overcome tumor chemoresistance.
添加收藏
创建看单
引用
2区Q1影响因子: 6.1
跳转PDF
登录
英汉
39. Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis.
期刊:Journal of translational medicine
日期:2025-02-28
DOI :10.1186/s12967-025-06246-3
BACKGROUND:Cancer-associated fibroblasts (CAFs) have been identified to drive chemotherapy resistance in triple-negative breast cancer (TNBC). This study evaluated the functions of CAFs-mediated suppressive ferroptosis in doxorubicin (DOX) resistance in TNBC and its detailed molecular mechanisms. METHODS:TNBC cell lines were co-cultured with CAFs isolated from DOX-sensitive (CAF/S) or DOX-resistant (CAF/R) breast cancer tissues. Cell viability and death were assessed by cell counting Kit-8 (CCK-8) and propidium iodide (PI) staining. Ferroptosis was evaluated by detection of Fe, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species (ROS) levels. Histone lactylation was determined by lactate production, pan-Kla and H3K18la expression. Molecular mechanism was determined by chromatin immunoprecipitation (ChIP) and dual luciferase reporter system. Molecule and protein expression was detected by quantitative Real-Time PCR (RT-qPCR), Western blotting, immunofluorescence and immunohistochemical staining. TNBC cells were injected into the mammary fat pad of nude mice to investigate DOX sensitivity in vivo. RESULTS:CAFs-derived lactate repressed ferroptosis to confer resistance of TNBC cells to DOX. Moreover, zinc finger protein 64 (ZFP64) expression was elevated in DOX-resistant TNBC and was associated with high histone lactylation level. CAFs facilitated histone lactylation to enhance ZFP64 expression, which triggered ferroptosis inhibition and DOX resistance. In addition, ZFP64 bound to the promoters of GTP cyclohydrolase-1 (GCH1) and ferritin heavy chain 1 (FTH1), thereby promoting their expression. Rescue experiments indicated that ZFP64 silencing-induced ferroptosis and high sensitivity of TNBC cells to DOX could be counteracted by GCH1 or FTH1 overexpression. CONCLUSION:CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe consumption.
添加收藏
创建看单
引用
1区Q1影响因子: 10.7
打开PDF
登录
英汉
40. NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.
期刊:Redox biology
日期:2024-12-19
DOI :10.1016/j.redox.2024.103479
Lactate-mediated lactylation on target proteins is recently identified as the novel posttranslational modification with profound biological functions. RNA 5-methylcytosine (mC) modification possesses dynamic and reversible nature, suggesting that activity of its methyltransferase NSUN2 is actively regulated. However, how NSUN2 activity is response to acidic condition in tumor microenvironment and then regulates cancer cell survival remain to be clarified. Here, we demonstrate that NSUN2 activity is enhanced by lactate-mediated lactylation at lysine 508, which then targets glutamate-cysteine ligase catalytic subunit (GCLC) mRNA to facilitates GCLC mC formation and mRNA stabilization. The activated GCLC induces higher level of intracellular GSH accompanied by decreased lipid peroxidation and resistant phenotype to ferroptosis induction by doxorubicin (Dox) in gastric cancer cells. Specifically, the effect of NSUN2 lactylation-GCLC-GSH pathway is nearly lost when NSUN2 K508R or GCLC C-A mutant (five cytosine sites) was introduced into the cancer cells. We further identify the catalytic subunit N-α-acetyltransferase 10 (NAA10) as the lactytransferase of NSUN2, and lactate treatment substantially enhances their association and consequent NSUN2 activation. Taken together, our findings convincingly elucidate the signaling axis of NAA10-NSUN2-GCLC that potently antagonizes the ferroptosis under acidic condition, and therefore, targeting NSUN2 lactylation might be an effective strategy in improving the prognosis of cancer patients.
添加收藏
创建看单
引用
1区Q1影响因子: 14.3
打开PDF
登录
英汉
41. Lactylation of HDAC1 Confers Resistance to Ferroptosis in Colorectal Cancer.
Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti-ferroptosis therapy. Through drug screening, it is found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically suppresses CRC growth both in vivo and in vitro. Mechanically, HDACi reduces ferroptosis suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, it is confirmed that HDACi specifically targets HDAC1 and promotes the H3K27ac modification of fat mass- and obesity-associated gene (FTO) and AlkB Homolog 5, RNA Demethylase (ALKBH5), which results in significant activation of FTO and ALKBH5. The activation of FTO and ALKBH5 reduces N6-methyladenosine (mA) modification on FSP1 mRNA, leading to its degradation. Crucially, lactylation of HDAC1 is essential for ferroptosis regulation. Both Vorinostat (SAHA) and Trichostatin A (TSA) notably diminish HDAC1 lactylation in comparison to other HDAC1 inhibitors, exhibiting a consistent trend of increasing susceptibility to ferroptosis. In conclusion, the research reveals that HDACi decreases HDAC1 lactylation to sensitize CRC to ferroptosis and that the combination of HDACi and ferroptosis inducers can be a promising therapeutic strategy for CRC.
添加收藏
创建看单
引用
1区Q1影响因子: 10.7
跳转PDF
登录
英汉
42. Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation.
期刊:Redox biology
日期:2025-02-15
DOI :10.1016/j.redox.2025.103553
Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate levels after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC caused by sublethal HS remains unclear. Here, we found that the metastatic potential of HCC increased in a lactate-dependent manner after IMWA. Moreover, sublethal HS triggered an increase in H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By performing an integrated analysis of proteomic and transcriptomic profiles, we revealed that HCC cells exhibited increased intracellular iron ion homeostasis and developed resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, an increase in H3K18la modification enhanced the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis after IMWA. Knocking down NFS1 diminished the metastatic potential of sublethally heat-treated HCC cells. Additionally, NFS1 deficiency exhibited a synergistic effect with oxaliplatin, leading to the significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of sublethal HS treatment. In conclusion, our study revealed the oncogenic role of histone lactylation in HCC after IMVA. We also bridged histone lactylation with ferroptosis, providing novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 6.1
英汉
43. Adjuvant chemotherapy in localized, resectable extremity and truncal soft tissue sarcoma and survival outcomes - A systematic review and meta-analysis of randomized controlled trials.
期刊:Cancer
日期:2025-03-01
DOI :10.1002/cncr.35792
INTRODUCTION:The role of adjuvant chemotherapy in localized, resectable soft tissue sarcomas (STSs) remains controversial. Despite positive findings reported in previous meta-analyses, the majority of randomized controlled trials (RCTs) fail to show a meaningful benefit. We conducted an updated meta-analysis to reassess the role of adjuvant chemotherapy in treating localized, resectable STSs. METHODS:A comprehensive literature review was conducted to identify RCTs that compared local therapy (surgery with or without radiotherapy) to local therapy with adjuvant chemotherapy. Articles were independently reviewed, and risk of bias was assessed by two authors. The outcomes assessed were overall survival (OS) and disease-free survival (DFS). The meta-analysis was performed using a random effects model (to account for possible heterogeneity across studies) for survival endpoints with the inverse-variance method, in which each study is weighted with the inverse of the variance of its effect estimate. RESULTS:A total of 19 RCTs comprising 2128 patients were included. Our study found that adjuvant chemotherapy improved OS (hazard ratio [HR], 0.80; p = .002) and DFS (HR, 0.78; p = .002). Doxorubicin-based monotherapy significantly improved OS (HR, 0.80; p = .01) and DFS (HR, 0.74; p = .0003), whereas doxorubicin-ifosfamide combined therapy did not significantly improve OS (HR, 0.78; p = .078) or DFS (HR, 0.94; p = .770). Doxorubicin-based ifosfamide combined therapy had moderate heterogeneity across studies. CONCLUSION:This study partially supports the benefit of adjuvant chemotherapy in the treatment of localized, resectable STSs. Nevertheless, because of the heterogeneity of STSs, the benefit and the risks of treatment with adjuvant chemotherapy need to be evaluated on an individual benefit-risk basis.
添加收藏
创建看单
引用
1区Q1影响因子: 10
跳转PDF
登录
英汉
44. The Landscape of Alterations from 1407 Ultra-Rare Sarcomas from the AACR GENIE Database: Clinical Implications.
期刊:Clinical cancer research : an official journal of the American Association for Cancer Research
日期:2023-11-14
DOI :10.1158/1078-0432.CCR-23-0876
PURPOSE:Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS. EXPERIMENTAL DESIGN:Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data. RESULTS:Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most common copy-number variations included deletions of CDKN2A and CDKN2B and amplifications of MDM2 and CDK4. TMB was generally low across all four categories of sarcoma, though there was considerable heterogeneity, with 3.8% of ST URS and 0.55% of bone URS having high TMB. We find Level 1 alterations (FDA-recognized biomarker predictive of response to an FDA-approved drug) in 10.0% of ST URS compared with 7.1% of ST non-URS, 1.1% of bone URS, and 4.5% of bone non-URS. Level 1-3 alterations (also include alterations for which there are standard-of-care drugs or clinical evidence supporting a drug) were seen in 27.8% of ST URS, 25.2% of ST non-URS, 20.9% of bone URS, and 17.4% of bone non-URS. CONCLUSIONS:Clinically actionable genomic alterations are seen in a substantial fraction of URS. Clinical sequencing in advanced URS has the potential to guide the treatment of a significant portion of patients with URS.
添加收藏
创建看单
引用
1区Q1影响因子: 7.6
英汉
45. Conference on challenges in sarcoma (CCS) 2024: Expert opinions on non-evidence-based management aspects.
期刊:European journal of cancer (Oxford, England : 1990)
日期:2025-03-17
DOI :10.1016/j.ejca.2025.115368
BACKGROUND:Soft tissue sarcomas (STS) and other mesenchymal tumours belong to rare, heterogeneous neoplasms with over 150 subtypes that pose significant challenges in diagnosis and clinical decision making. While guidelines address evidence-based diagnostic and therapeutic procedures, clinical situations and scenarios without evidence remain controversial in daily practice. The 2024 Conference on Challenges in Sarcoma (CCS2024) aimed to narrow these gaps with the support of an international and multidisciplinary panel of sarcoma experts. METHODS:A Delphi process identified 200 controversial questions across eight prioritised clinical scenarios, including tenosynovial giant cell tumour, synovial sarcoma of the extremities, retroperitoneal sarcomas, angiosarcoma, phyllodes tumour, malignant peripheral nerve sheath tumour, uterine leiomyosarcoma, and atypical lipomatous tumour. RESULTS:Sixty-four experts discussed 141 controversies during the conference and reached strong consensus (> 90 %) on 24 and consensus (> 75 %) on 45 key diagnostic and therapeutic issues, while unresolved controversies emphasized the need for further research. CONCLUSIONS:CCS2024 provides a framework for clinical decision making and underscores the importance of consensus-driven approaches in the treatment of rare and complex malignancies.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
46. Regulatory T cells in immune checkpoint blockade antitumor therapy.
期刊:Molecular cancer
日期:2024-11-08
DOI :10.1186/s12943-024-02156-y
Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs' activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer's development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs' involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies.
添加收藏
创建看单
引用
1区Q1影响因子: 45.5
英汉
47. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
期刊:Cell
日期:2024-10-16
DOI :10.1016/j.cell.2024.09.032
Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53 TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1 immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.
添加收藏
创建看单
引用
1区Q1影响因子: 16.1
英汉
48. Innate Immune Activation with Multifunctional Nanoparticles for Cancer Immunotherapy.
期刊:Angewandte Chemie (International ed. in English)
日期:2025-01-10
DOI :10.1002/anie.202423280
Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers by leveraging the immune system to combat malignancies. However, its efficacy is limited by the immunosuppressive tumor microenvironment and other regulatory mechanisms of the immune system. Innate immune modulators (IIMs) provide potent immune activation to complement adaptive immune responses and help overcome resistance to ICB. This minireview provides an overview of IIMs and their roles in antitumor immune responses and summarizes recent advances in developing nanotechnology to enhance the delivery of IIMs to tumors for potentiating cancer immunotherapy and mitigating systemic toxicity. We discuss innovative nanoparticle platforms for the delivery of IIMs targeting the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the toll-like receptor pathway, and the retinoic acid-inducible gene I-like receptor pathway. We review the preliminary clinical readouts of representative IIM nanoptherapeutics and highlight the development of multifunctional nanoparticles for combination treatments of IIMs with conventional treatment mdoalities such as chemotherapy, radiotherapy, photodynmic therapy, and tumor antigens. Finally, we summarize the lessons learned from the existing systems, the challenges in the field, and future perspectives for this exciting field of nanotherapeutics for cancer immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 98.4
打开PDF
登录
英汉
49. Pancreatic cancer.
期刊:Lancet (London, England)
日期:2025-04-05
DOI :10.1016/S0140-6736(25)00261-2
Pancreatic cancer is frequently a lethal disease with an aggressive tumour biology often presenting with non-specific symptoms. Median survival is approximately 4 months with a 5-year survival of 13%. Surveillance is recommended in individuals with familial pancreatic cancer, specific mutations, and high-risk intraductal papillary mucinous neoplasm, as they are at high risk of developing pancreatic cancer. Chemotherapy combined with surgical resection remains the cornerstone of treatment. However, only a small subset of patients are candidates for surgery. Multi-agent chemotherapy has improved survival in the palliative setting for patients with metastatic disease, as (neo)adjuvant and induction therapy have in patients with borderline resectable and locally advanced pancreatic. Given that pancreatic cancer is predicted to become the second leading cause of cancer-related death by 2030, novel therapies are urgently needed.
添加收藏
创建看单
引用
1区Q1影响因子: 28.1
跳转PDF
登录
英汉
50. LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer.
期刊:Cell research
日期:2025-01-02
DOI :10.1038/s41422-024-01025-z
Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.
添加收藏
创建看单
引用
1区Q1影响因子: 6.4
英汉
51. Hypofractionated Preoperative Radiation Therapy for Soft Tissue Sarcoma: A Systematic Review.
期刊:International journal of radiation oncology, biology, physics
日期:2024-08-05
DOI :10.1016/j.ijrobp.2024.07.2151
PURPOSE:Hypofractionated radiation therapy is being used more frequently for many common cancer sites. Conventionally fractionated radiation therapy treatment regimens have remained the standard of care when radiation therapy is indicated for soft tissue sarcoma (STS). The aim of this study was to systematically review published data on the use of preoperative hypofractionated radiation therapy as part of a curative treatment paradigm in patients with STS. Herein, we summarize current evidence for the use of hypofractionated radiation therapy in the preoperative treatment of STS. METHODS AND MATERIALS:We conducted a database search for prospectively or retrospectively collected data on patients with a diagnosis of STS treated with hypofractionated radiation therapy. Studies evaluating STS of all histologic subtypes affecting extremities or trunks were included in the search. Articles were screened by 2 independent reviewers for inclusion in this review. Patient, treatment, toxicity, and outcome data were recorded and collated from selected studies. RESULTS:Twenty-five articles are included in this review. Nine prospective trials have been published since 2020. Dose fractionations range from 25 to 40 Gy in 5 fractions or 28-42.75 Gy in 8-15 fractions. Local control and overall survival outcomes are consistent with historical data for conventionally fractionated radiation therapy. Acute toxicity and wound complication rates are in keeping with acceptable results. Late toxicity data are limited and require longer follow-up. Rates of pathologic complete response are promising across all studies. CONCLUSIONS:There is a growing body of evidence supporting hypofractionation as safe and effective in the preoperative treatment of STS. This review highlights potential areas that could be further investigated to optimize preoperative treatment for STS.
添加收藏
创建看单
引用
2区Q1影响因子: 6.4
跳转PDF
登录
英汉
52. Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.
期刊:British journal of cancer
日期:2024-06-05
DOI :10.1038/s41416-024-02672-0
BACKGROUND:British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS:A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION:Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).
Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors, including in soft-tissue sarcoma (STS). However, the ideal combination of treatment modalities remains to be determined, and reliable biomarkers to predict which patients will benefit are lacking. Here, we report the results of the STS cohort of the SABR-PDL1 phase II trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy (SBRT) delivered concurrently with the 2nd cycle to at least one tumor site. Eligible patients received atezolizumab until progression or unmanageable toxicity, with SBRT at 45 Gy in 3 fractions). The primary endpoint was one-year progression-free survival (PFS) rate with success defined as 13 patients achieving 1-year PFS. Sixty-one heavily pretreated patients with STS (median 5 prior lines; 52% men; median age 54 years; 28% leiomyosarcoma) were enrolled across two centers (France, Spain). SBRT was delivered to 55 patients (90%), with the lung being the most commonly irradiated site (50%). After a median follow-up of 45 months, the one-year PFS rate was 8.3% [95% CI: 3.6-18.1]. Median PFS and overall survival were 2.5 and 8.6 months, respectively. Best responses included partial responses (5%) and stable disease (60%). Immune profiling revealed increased immunosuppressive tumor-associated macrophages (e.g., IL4I1, HES1) and monocyte-recruiting chemokines in non-responders. Higher monocyte/lymphocyte ratios (MonoLR) in tumor and blood correlated with progression. PD-L1 status, lymphoid infiltration, and tertiary-lymphoid structures were not predictive. Although the primary endpoint was not met, this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy. EudraCT No. 2015-005464-42; Clinicaltrial.gov number: NCT02992912.
添加收藏
创建看单
引用
2区Q1影响因子: 6.3
跳转PDF
登录
英汉
54. Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes.
期刊:Neoplasia (New York, N.Y.)
日期:2024-12-15
DOI :10.1016/j.neo.2024.101104
Fibrosarcomas (FSA) are malignant mesenchymal tumors characterized by low chemo- and radiosensitivity. Development of novel treatment strategies for human adult FSA is hindered by the low incidence and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, hence potentially representing a clinically amenable model to assess novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNAsequencing and liquid chromatography-tandem mass spectrometry, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and adult FSA allows identification of tumor targets that are conserved across species. Significant enrichment in DNA repair pathways in feline FSA correlate with aggressive clinical behavior in human soft-tissue sarcoma. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease.
添加收藏
创建看单
引用
1区Q1影响因子: 8.6
跳转PDF
登录
英汉
55. Evaluating [Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.
期刊:European journal of nuclear medicine and molecular imaging
日期:2024-07-15
DOI :10.1007/s00259-024-06809-4
PURPOSE:Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. METHODS:[Ga]Ga- and [Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. RESULTS:[Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. CONCLUSION:[Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
英汉
56. Tumour atlases enable researchers to navigate through cancers.
期刊:Nature
日期:2024-10-30
DOI :10.1038/d41586-024-03498-9
添加收藏
创建看单
引用
1区Q1影响因子: 29.5
跳转PDF
登录
英汉
57. Mature B, T and NK-cell, plasma cell and histiocytic/dendritic cell neoplasms: classification according to the World Health Organization and International Consensus Classification.
期刊:Journal of hematology & oncology
日期:2024-07-08
DOI :10.1186/s13045-024-01570-5
In 2022, two updated classification systems for lymphoid neoplasms were published by the World Health Organization (WHO Classification of Haematolymphoid Tumours, 5th edition, referred to hereafter as WHO-HAEM5) and the International Consensus Conference (ICC) (Alaggio et al. in Leukemia 36(7):1720-1748, 2022; Campo et al. in Blood 140(11):1229-1253, 2022). Both classifications were conceived by both pathologists and clinicians with expertise in the field. The reasons for this have been reviewed previously (Arber et al. in Virchows Arch 482(1):1-9, 2023; Cree in Leukemia 36(7):1701-1702, 2022, Leukemia 36(11):2750, 2022). Given that both groups were using data-driven processes and consensus and used the revised 4th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM4R) as a starting point, it is not entirely surprising that the resulting classifications are quite similar. However, they are not identical and reflect preferences or approaches for certain unsettled areas as well as preferred terminology. In this review, we will compare nomenclature of the WHO-HAEM5 and ICC classifications, focusing on lymphoid neoplasms and lymphoproliferative disorders (LPDs).
BACKGROUND:Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling. METHODS:Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately. RESULTS:Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively). CONCLUSIONS:We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
59. Rational Design of Metal-Organic Frameworks for Pancreatic Cancer Therapy: from Machine Learning Screening to In Vivo Efficacy.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2025-02-02
DOI :10.1002/adma.202412757
Despite improvements in cancer survival rates, metastatic and surgery-resistant cancers, such as pancreatic cancer, remain challenging, with poor prognoses and limited treatment options. Enhancing drug bioavailability in tumors, while minimizing off-target effects, is crucial. Metal-organic frameworks (MOFs) have emerged as promising drug delivery vehicles owing to their high loading capacity, biocompatibility, and functional tunability. However, the vast chemical diversity of MOFs complicates the rational design of biocompatible materials. This study employed machine learning and molecular simulations to identify MOFs suitable for encapsulating gemcitabine, paclitaxel, and SN-38, and identified PCN-222 as an optimal candidate. Following drug loading, MOF formulations are improved for colloidal stability and biocompatibility. In vitro studies on pancreatic cancer cell lines have shown high biocompatibility, cellular internalization, and delayed drug release. Long-term stability tests demonstrated a consistent performance over 12 months. In vivo studies in pancreatic tumor-bearing mice revealed that paclitaxel-loaded PCN-222, particularly with a hydrogel for local administration, significantly reduced metastatic spread and tumor growth compared to the free drug. These findings underscore the potential of PCN-222 as an effective drug delivery system for the treatment of hard-to-treat cancers.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
60. Advances in Vulvar Cancer Biology and Management.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2024-10-31
DOI :10.1200/JCO.24.01071
PURPOSE:Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC. DESIGN:We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC. RESULTS:Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV-) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV-/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design. CONCLUSION:Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.
添加收藏
创建看单
引用
1区Q1影响因子: 56.7
英汉
61. Unveiling targets and resistance in FGFR-altered cancers.
期刊:Annals of oncology : official journal of the European Society for Medical Oncology
日期:2025-01-10
DOI :10.1016/j.annonc.2025.01.002
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
打开PDF
登录
英汉
62. Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion.
期刊:Cancer cell
日期:2024-10-10
DOI :10.1016/j.ccell.2024.09.009
Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers.
添加收藏
创建看单
引用
1区Q1影响因子: 63.1
跳转PDF
登录
英汉
63. Endometriosis Typology and Ovarian Cancer Risk.
期刊:JAMA
日期:2024-08-13
DOI :10.1001/jama.2024.9210
Importance:Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. Objective:To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. Design, Setting, and Participants:Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Exposures:Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Main Outcomes and Measures:Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. Results:In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Conclusions and Relevance:Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.
添加收藏
创建看单
引用
1区Q1影响因子: 81.1
英汉
64. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.
期刊:Nature reviews. Clinical oncology
日期:2025-04-03
DOI :10.1038/s41571-025-01015-z
Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumour types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The prevalence of the MSI-H/dMMR phenotype is highest in endometrial and colorectal cancers, and this phenotype is associated with a distinct tumour biology, prognosis and responsiveness to various anticancer treatments. In a minority of patients, MSI-H/dMMR cancers result from an inherited pathogenic variant in the context of Lynch syndrome, which has important implications for familial genetic screening. Whether these hereditary cancers have a different biology and clinical behaviour to their sporadic counterparts remains uncertain. Interest in this tumour molecular subtype has increased following the discovery of the high sensitivity of metastatic MSI-H/dMMR cancers to immune-checkpoint inhibitors (ICIs) in a histology-agnostic manner, which reflects the genomic hypermutation resulting from dMMR that renders these tumours highly immunogenic and immune infiltrated. This vulnerability is now also being exploited in early stage disease settings. Despite this common biological foundation, different MSI-H/dMMR cancers have histotype-specific features that correspond to their particular cell or tissue of origin, which might be associated with differences in prognosis and sensitivity to ICIs. In this Review, we provide an overview of the epidemiology, biology, pathogenesis, clinical diagnosis and treatment of MSI-H/dMMR tumours as a histology-agnostic cancer phenomenon. We also highlight peculiarities associated with specific pathogenetic alterations and histologies of MSI-H/dMMR tumours.
添加收藏
创建看单
引用
2区Q1影响因子: 5.7
跳转PDF
登录
英汉
65. Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma.
期刊:Frontiers in immunology
日期:2025-03-12
DOI :10.3389/fimmu.2025.1557006
Background:Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors. Methods:We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist to expand nonselected TILs in 2-3 weeks, then rapidly expanded them over 2 weeks. Their phenotypes were characterized using flow cytometry. Their antitumor activity was validated using cytotoxic T lymphocyte assays measuring CD107a on the TILs and the viability of tumor cells and using an autologous patient-derived xenograft (PDX) tumor model. Results:We successfully expanded TILs in > 90% of collected samples. TILs generated preferentially increased CD8+ T cells but suppressed CD4+ T cells. A small portion of TILs were resident memory T cells. The expanded TILs reduced autologous tumor cells by 37.5% within 24 hours. Infusion of TILs in mice bearing autologous PDX tumors strongly inhibited liposarcoma growth. FDA has approved use of this GMP-feasible protocol in our clinical trial (IND 30562). Conclusion:It is feasible to generate antitumor TILs using CD3/CD28 activator to replace the unavailable anti-CD137 agonist. Our study supports the further development of TIL-based therapy.
添加收藏
创建看单
引用
1区Q1影响因子: 6.1
英汉
66. Vascular endothelial growth factor and programmed cell death-1 inhibition in bone sarcomas.
期刊:Cancer
日期:2024-11-28
DOI :10.1002/cncr.35668
添加收藏
创建看单
引用
1区Q1影响因子: 10.3
跳转PDF
登录
英汉
67. IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors.
期刊:Journal for immunotherapy of cancer
日期:2024-11-20
DOI :10.1136/jitc-2024-009743
BACKGROUND:Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs). METHODS:To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. RESULTS:We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells. CONCLUSIONS:Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.
添加收藏
创建看单
引用
1区Q1影响因子: 6.9
跳转PDF
登录
英汉
68. Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling.
期刊:Oncogene
日期:2024-11-01
DOI :10.1038/s41388-024-03199-7
Ewing sarcoma (ES) is characterized by EWS::FLI1 or EWS::ERG fusion proteins. Knowing that ion channels are involved in tumorigenesis, this work aimed to study the involvement of the KCNN1 gene, which encodes the SK1 potassium channel, in ES development. Bioinformatics analyses from databases were used to study KCNN1 expression in patients and cell lines. Molecular approaches and in vitro assays were used to study the transcriptional regulation of KCNN1 and its involvement in the regulation of ES cell proliferation. KCNN1 is overexpressed in ES patient biopsies, and its expression is inversely correlated with patient survival. EWS::FLI1, like EWS::ERG, promotes KCNN1 and SK1 expression, binding to GGAA microsatellites near the promoter of KCNN1 isoforms. KCNN1 is involved in the regulation of ES cell proliferation, with its silencing being associated with a slowing of the cell cycle, and its expression modulates membrane potential and therefore calcium flux. These results highlight that KCNN1 is a direct target of EWS::FLI1 and EWS::ERG and demonstrate that KCNN1 is involved in the regulation of intracellular calcium activity and ES cell proliferation, making it a promising therapeutic target in ES.
添加收藏
创建看单
引用
1区Q1影响因子: 7.1
跳转PDF
登录
英汉
69. Sarcomas With RAD51B Fusions Are Associated With a Heterogeneous Phenotype.
期刊:Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
日期:2023-12-21
DOI :10.1016/j.modpat.2023.100402
RAD51B-rearranged sarcomas are rare neoplasms that exhibit a heterogeneous morphology. To date, 6 cases have been reported, all involving the uterus, including 4 perivascular epithelioid cell tumors (PEComas) and 2 leiomyosarcomas (LMS). In this study, we describe the morphologic, immunohistochemical, and molecular features of 8 additional sarcomas with RAD51B rearrangement, including the first extrauterine example. All patients were women with a median age of 57 years at presentation. Seven tumors originated in the uterus, and one in the lower extremity soft tissue, with a median tumor size of 12 cm. Histologically, 4 tumors showed predominantly spindle cell morphology with eosinophilic fibrillary cytoplasm, with or without nuclear pleomorphism, whereas 2 tumors exhibited pleomorphic epithelioid cells, featuring clear to eosinophilic, granular cytoplasm. Two neoplasms exhibited undifferentiated cytomorphology, including one with uniform small blue round cells. All tumors showed high-grade cytologic atypia and high mitotic activity (median: 30/10 high-power fields), whereas coagulative necrosis was noted in 6 cases and lymphovascular invasion in 2. By immunohistochemistry, 2 showed myoid and melanocytic markers in keeping with PEComa, whereas 4 cases were only positive for smooth muscle markers consistent with LMS (including 3 myxoid). The remaining 2 cases had a nonspecific immunoprofile. Five cases tested by targeted RNA sequencing (Archer FusionPlex, Illumina TruSight) showed different fusion partners (HMGA2, PDDC1, and CEP170). RAD51B rearrangements were identified by FISH in the remaining 3 cases. Targeted DNA sequencing in 2 cases was negative for TSC gene alterations. Clinical outcome, available in 5 patients (median follow-up, 19 months), revealed 3 local recurrences, 2 lung metastases, and 4 deaths due to disease. Our results expand the spectrum of sarcomas with RAD51B fusions, demonstrating variable clinical presentations, morphologic spectrum, and fusion partners. These tumors have a predilection for a uterine location, with either LMS, PEComa, or undifferentiated phenotypes, and are associated with an aggressive clinical course.
添加收藏
创建看单
引用
1区Q1影响因子: 23
跳转PDF
登录
英汉
70. Spatial dissection of tumour microenvironments in gastric cancers reveals the immunosuppressive crosstalk between fibroblasts and -activated macrophages.
期刊:Gut
日期:2025-04-07
DOI :10.1136/gutjnl-2024-332901
BACKGROUND:A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC). OBJECTIVE:Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells. DESIGN:We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME. RESULTS:GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that -expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. fibroblasts and -activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that fibroblasts recruit myeloid cells and stimulate activation in recruited macrophages. The development of immunosuppressive TME by fibroblasts were also validated in syngeneic mouse models. CONCLUSION:GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between fibroblasts and -activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
71. Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers.
期刊:Molecular cancer
日期:2025-03-14
DOI :10.1186/s12943-025-02256-3
We report proteogenomic analysis of locally advanced cervical cancer (LACC). Exome-seq data revealed predominant alterations of keratinization-TP53 regulation and O-glycosylation-TP53 regulation axes in squamous and adeno-LACC, respectively, compared to in early-stage cervical cancer. Integrated clustering of mRNA, protein, and phosphorylation data identified six subtypes (Sub1-6) of LACC among which Sub3, 5, and 6 showed the treatment-resistant nature with poor local recurrence-free survival. Elevated immune and extracellular matrix (ECM) activation mediated by activated stroma (PDGFD and CXCL1 fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AC epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10 ECs. We further demonstrated that CIC mutations could trigger EMT activation by upregulating ETV4, and the elevation of the immune checkpoint PVR and neutrophil-like myeloid-derived suppressive cells (FCN1 and FCGR3B macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AC ECs. These results provide a battery of somatic mutations, cellular pathways, and cellular players that can be used to predict treatment-resistant LACC subtypes and can serve as potential therapeutic targets for these LACC subtypes.
添加收藏
创建看单
引用
2区Q1影响因子: 6
跳转PDF
登录
英汉
72. Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing.
期刊:Antioxidants (Basel, Switzerland)
日期:2024-05-10
DOI :10.3390/antiox13050587
Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.
添加收藏
创建看单
引用
3区Q1影响因子: 9.6
英汉
73. 18 F-FDG PET Metabolic Parameters for the Prediction of Histological Response to Induction Chemotherapy in Osteosarcoma and Ewing Sarcoma : A Systematic Review and Network Meta-analysis.
期刊:Clinical nuclear medicine
日期:2024-09-25
DOI :10.1097/RLU.0000000000005412
PURPOSE:This study aimed to evaluate the ability of 18 F-FDG PET/CT metabolic parameters to predict the histological response to neoadjuvant chemotherapy in patients with osteosarcoma and Ewing sarcoma. PATIENTS AND METHODS:This systematic review and network meta-analysis adhered to the PRISMA-NMA and Cochrane guidelines. Electronic databases were searched from January 2008 to January 2024; this search was supplemented by snowballing methods. The risk of bias was evaluated with QUADAS-2, and evidence certainty was assessed using the GRADE approach. The prognostic value of 18 F-FDG PET/CT parameters, including pretreatment and posttreatment SUVs (SUV1, SUV2 and the SUV2/SUV1 ratio), metabolic tumor volume (MTV1, MTV2, ΔMTV), and total lesion glycolysis (TLG1, TLG2, ΔTLG), was examined. RESULTS:The meta-analysis of 18 studies (714 patients) identified the ΔTLG, ΔMTV, and SUV ratio as superior predictors of histological response. The changes in metabolic activity, as indicated by these parameters, provided a robust indication of treatment effectiveness. Baseline parameters showed limited predictive value compared with posttreatment assessments. The study's robustness was confirmed through meta-regression, which revealed that the predictive value of the SUV2 and SUV ratio was consistent across various cutoff thresholds. CONCLUSIONS:18 F-FDG PET/CT metabolic parameters, particularly those measuring changes posttherapy, are effective in predicting the histological response in patients with osteosarcoma and Ewing sarcoma. These findings underscore the potential of 18 F-FDG PET/CT in guiding early treatment decisions, thereby enhancing personalized therapeutic approaches.
添加收藏
创建看单
引用
2区Q1影响因子: 5.6
英汉
74. Alternative driver pathways in peripheral nerve sheath tumors - including DICER1 and/or KRAS alterations.
75. Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.
期刊:Nature cancer
日期:2024-04-24
DOI :10.1038/s43018-024-00749-6
In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10 T cells per m after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10 CAR T cells per m after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .
添加收藏
创建看单
引用
1区Q1影响因子: 23
英汉
76. Endoscopic papillectomy versus surgical ampullectomy for adenomas and early cancers of the papilla: a retrospective Pancreas2000/European Pancreatic Club analysis.
期刊:Gut
日期:2025-02-06
DOI :10.1136/gutjnl-2022-327996
OBJECTIVE:Ampullary neoplastic lesions can be resected by endoscopic papillectomy (EP) or transduodenal surgical ampullectomy (TSA) while pancreaticoduodenectomy is reserved for more advanced lesions. We present the largest retrospective comparative study analysing EP and TSA. DESIGN:Of all patients in the database, lesions with prior interventions, benign histology advanced malignancy (T2 and more), patients with hereditary syndromes and those undergoing pancreatoduodenectomy were excluded. All remaining cases as well as a subgroup of them, after propensity-score matching (nearest-neighbour-method) based on age, gender, anthropometrics, comorbidities, size and histological subtype, were analysed. The median follow-up was 21 months (IQR 10-47) after the primary intervention. Primary outcomes were rates of complete resection (R0) and complications. Groups were compared by Fisher's exact or χ test, Mann-Whitney-U-test and log-rank test for survival. RESULTS:Of 1673 patients in the database, 1422 underwent EP and 251 TSA. Of them, 23.2% were excluded for missing or inconclusive data and 19.8% of patients for prior interventions or hereditary syndromes. Final histology showed in 24.2% of EP and 14.8% of TSA patients a histology other than adenoma or adenocarcinoma while advanced cancers were recorded in 10.9% of EP and 36.6% of TSA patients. Finally, 569 EP and 63 TSA were included in the overall analysis, with a higher rate of more advanced cases and higher R0 resection rates in the TSA groups (90.5% vs 73.1%; p<0.01), with additional ablation in the EP group in 14.4%. Severe adverse event rates were 3.2% (TSA) vs 1.9% (EP). Recurrence after histological R0 resection was 16% (EP) vs 3.2% (TSA; p=0.01), and additional therapy for R1 resection was applied in 67% of the 159 cases. Propensity-score-based matching identified 62 pairs of EP/TSA patients with comparable baseline patient and lesion characteristics. The initial R0-rate was 72.6% (EP) compared with 90.3% (TSA, p=0.02) with recurrences found in 8% (EP) vs 3.2% (TSA; p=0.07); reinterventions were more frequent in the EP group. Overall survival was comparable. CONCLUSIONS:The rate of patients with poor indications due to non-neoplastic disease or advanced cancer is still high for both EP and TSA; multiple retreatments were necessary for EP. Although EP can be considered an appropriate primary therapy for certain ampullary adenomas, case selection for both therapies (especially with regard to the best step-up approach) should be studied further.
添加收藏
创建看单
引用
1区Q1影响因子: 63.1
跳转PDF
登录
英汉
77. Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis.
期刊:JAMA
日期:2024-06-11
DOI :10.1001/jama.2024.5814
Importance:Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening. Objective:To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening. Design, Setting, and Participants:This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer. Exposures:Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening. Main Outcomes and Measures:End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis. Results:The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004). Conclusions and Relevance:In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.
添加收藏
创建看单
引用
1区Q1影响因子: 56.7
英汉
78. Decaffeinated coffee consumption and risk of total and site-specific cancer.
期刊:Annals of oncology : official journal of the European Society for Medical Oncology
日期:2025-04-01
DOI :10.1016/j.annonc.2025.03.018
BACKGROUND:Coffee is generally considered safe regarding cancer risk. However, concerns have emerged over methylene chloride, a chemical used in decaffeination, due to its carcinogenic properties. The potential cancer risk from methylene chloride residue in decaffeinated coffee remains unclear. PATIENTS AND METHODS:This prospective cohort study included 75 988 women (Nurses' Health Study, 1984-2020) and 45 349 men (Health Professionals Follow-up Study, 1986-2020). Decaffeinated coffee consumption was assessed at baseline and every 4 years using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of total and 14 site-specific cancers associated with decaffeinated coffee consumption, adjusted for regular coffee intake and other potential confounding variables. RESULTS:During up to 36 years of follow-up, we documented 34 120 incident cancer cases (22 688 in women and 11 432 in men). Overall, decaffeinated coffee intake was not associated with higher total cancer risk [per 1 cup/day higher intake, HR 1.00 (95% CI 0.98-1.01)]. For specific cancer type, an inverse association was observed for colorectal [HR 0.96 (95% CI 0.92-0.99)] and aggressive prostate [HR 0.93 (95% CI 0.87-0.99)] cancer. An observed higher lung cancer risk for decaffeinated coffee attenuated to null when restricted to never smokers. However, we observed elevated bladder cancer risk among male never smokers: compared with nondrinkers, 0.1-0.9, 1-1.9, 2-2.9 and ≥3 cups/day of decaffeinated coffee intake were associated with HRs of 1.30 (95% CI 1.01-1.68), 1.42 (95% CI 1.00-2.03), 1.43 (95% CI 0.91-2.23), and 1.79 (95% CI 0.92-3.50), respectively, with borderline significant linear trends (P = 0.06). This positive association remained robust in various sensitivity analyses and became even stronger with an 8-year lag. No association between decaffeinated coffee and bladder cancer was observed among women (P = 0.03). CONCLUSIONS:Higher decaffeinated coffee intake was not associated with total cancer risk. However, the observed significant higher risk of bladder cancer in men warrants further studies.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
跳转PDF
登录
英汉
79. Photosensitive Hybrid γδ-T Exosomes for Targeted Cancer Photoimmunotherapy.
期刊:ACS nano
日期:2025-01-25
DOI :10.1021/acsnano.4c11024
Melanoma is the most aggressive type of skin cancers. Traditional chemotherapy and radiotherapy have limited effectiveness and can lead to systemic side effects. Photodynamic therapy (PDT) is a photoresponsive cancer therapy based on photosensitizers to generate reactive oxygen species (ROS) to eradicate tumor cells. Our previous study showed that exosomes derived from human γδ-T cells (γδ-T exosomes) could control Epstein-Barr virus-associated tumors. Here, we combined γδ-T exosomes and PDT for targeted photoimmunotherapy by membrane fusion of γδ-T exosomes and Chlorin e6 (Ce6)-loaded liposomes. The functional surface proteins, such as CCR5 and PD-1, on the hybrid exosomes mediated the specific binding of hybrid exosomes toward melanoma tissues. The cytolytic molecules, such as granzyme A, granzyme B, perforin, and granulysin from γδ-T exosomes, induced specific apoptosis of cancer cells without harming normal cells. In response to light irradiation, ROS generation inside melanoma cells synergized with cytolytic molecules to induce apoptosis and promote immunogenic cancer cell death (ICD). The subsequently released damage-associated molecular patterns (DAMPs) could stimulate human dendritic cell maturation and induce melanoma antigen-specific CD4 and CD8 T-cell responses, thereby enhancing antitumor immunity. This study provides a promising strategy by combining γδ-T exosomes and PDT for photoimmunotherapy, thereby expanding the clinical applications of γδ-T exosome therapy for cancer patients.
添加收藏
创建看单
引用
1区Q1影响因子: 45.5
英汉
80. Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2.
期刊:Cell
日期:2025-02-11
DOI :10.1016/j.cell.2025.01.025
Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β that dimerizes with integrin α and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.
添加收藏
创建看单
引用
2区Q1影响因子: 5.7
跳转PDF
登录
英汉
81. Single-cell RNA-seq reveals as a prognostic biomarker in low-grade endometrial stromal sarcoma.
期刊:Frontiers in immunology
日期:2024-11-29
DOI :10.3389/fimmu.2024.1513076
Background:Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine malignancy characterized by its complex tumor microenvironment (TME) and high recurrence rates, posing challenges to accurate prognosis and effective treatment. Identifying prognostic biomarkers is essential for improving patient stratification and guiding therapeutic strategies. Methods:Using single-cell transcriptome analysis combined with H&E and multiplex immunofluorescence staining, we identified a subpopulation of tumor cells in LG-ESS and further validated the association of this subpopulation and its characteristic genes with LG-ESS prognosis by molecular characterization and bulk transcriptome data. Results:Our analysis reveals multiple cellular subpopulations within the tumor tissue, particularly a tumor cell subpopulation among them which is associated with poor prognosis. Originating from normal stromal fibroblasts, this subpopulation appears to play a crucial role in TME remodeling, smooth muscle cell behavior, and potentially in tumorigenesis and metastasis. Of particular interest in this subpopulation is the highly expressed gene, which is significantly associated with a shortened survival in ESS, highlighting its potential as a prognostic biomarker. Conclusion:Our study reveals the complexity of TME within the LG-ESS and highlights the role that tumor cell subpopulations play in disease progression and patient prognosis. The identification of as a prognostic biomarker suggests a new approach for the personalized treatment and prognosis monitoring of patients.
添加收藏
创建看单
引用
1区Q1影响因子: 10
英汉
82. Anlotinib plus TQB2450, a PD-L1 Antibody, in Patients with Advanced Alveolar Soft Part Sarcoma: A Single-Arm, Phase II Trial.
期刊:Clinical cancer research : an official journal of the American Association for Cancer Research
日期:2024-12-16
DOI :10.1158/1078-0432.CCR-24-2444
PURPOSE:Alveolar soft part sarcoma (ASPS) is an ultrarare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in patients with ASPS. PATIENTS AND METHODS:This single-arm, phase II study evaluated the efficacy of TQB2450, an anti-PD-L1 agent, combined with anlotinib, a tyrosine kinase inhibitor, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response, progression-free survival, and overall survival. Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. RESULTS:The study enrolled 29 patients, of whom 28 were evaluable (one withdrew because of acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the duration of response was not reached, with an estimated median progression-free survival of 35.2 months. Grade 3 to 4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, TLS density, and CD20-positive immune cells. CONCLUSIONS:The combination of anlotinib and TQB2450 is effective and tolerable in patients with ASPS. TLS may serve as a prognostic biomarker, meriting further investigation.
添加收藏
创建看单
引用
1区Q1影响因子: 7.1
英汉
83. Erythroblastic Sarcoma in Adults and Children: Different Pathways to the Same Destination.
期刊:Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
日期:2025-02-14
DOI :10.1016/j.modpat.2025.100716
Erythroblastic sarcoma (ES), the mass-forming presentation of acute erythroid leukemia, is a rare and challenging diagnosis. Given the limited number of published cases, the diagnostic criteria, immunophenotype, and molecular characteristics are not well defined. We describe 56 cases of ES (36 adult and 11 pediatric cases from our cohort, and 9 pediatric cases from the literature). The median age was 60 years among adults and 1.8 years among children. An association with prior cytotoxic therapy or myeloid neoplasm was documented in 10/36 (28%) and 25/36 (69%) adults, respectively, but was not reported in children. Bones were the most common site of involvement among adults (16/36, 44%), whereas soft tissue or central nervous system involvement was most common among children (each 9/20, 45%). Adult and pediatric ES shared similar morphologic features with all cases showing mass formation of erythroblasts and/or involvement of body fluids. Immunophenotypic analysis showed that blasts were positive for CD71 (49/49, 100%), GLUT1 (12/12, 100%), CD43 (37/39, 95%), E-cadherin (38/44, 86%), and CD117 (39/51, 76%) but were mostly negative for CD45 (15/48, 31% positive). Strong and diffuse P53 expression was common among adults (21/24, 88%) and absent among children (3/10, 30% with dim/subset positivity). Although a complex karyotype was common in adult (15/17, 88%) and pediatric ES (8/12, 68%), TP53 mutations were exclusively seen in adult ES (17/19, 89%), at least 11 of which (65%) were biallelic. Instead, pediatric ES was enriched for gene fusions; specific fusions were identified in 10 cases, 7 of which involved NFIA rearrangement. The prognosis was poor among both age groups; 29/37 (78%) patients died from disease with a median overall survival of 3 months. Overall, these results show that adult and pediatric ES have overlapping morphologic and immunophenotypic features but distinct molecular profiles suggesting diverging pathogenesis.
添加收藏
创建看单
引用
1区Q1影响因子: 14.3
跳转PDF
登录
英汉
84. Targeting KIFC1 Promotes Senescence in Soft Tissue Sarcoma via FXR1-Dependent Regulation of MAD2L1 mRNA Stability.
Patients diagnosed with soft tissue sarcoma (STS) often present at intermediate to advanced stages, with inherently limited therapeutic options available. There is an urgent need to identify novel therapeutic targets. In this study, by screening STS data from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases, KIFC1 is identified as a potential biomarker and a promising therapeutic target for STS. Notably, a significant increase in KIFC1 levels, which exhibited a strong correlation with a poor prognosis in STS patients is observed. The findings revealed that knockout of KIFC1 suppressed STS growth both in vitro and in vivo. Furthermore, KIFC1 is found to regulate cellular senescence in STS, which has not been reported before. that targeting KIFC1 induced cellular senescence via interacting with FXR1, an RNA-binding protein is discovered, thereby further stabilizing MAD2L1 mRNA in an m6A-dependent manner. Additionally, the suppression of KIFC1 markedly diminished the growth of patient-derived xenografts (PDX) and triggered senescence. This study provides the first evidence that KIFC1 inhibition induces cellular senescence through MAD2L1, underscoring KIFC1 as a novel prognostic biomarker and a potential therapeutic target for STS.
添加收藏
创建看单
引用
2区Q1影响因子: 9.7
英汉
85. Dimensional assessment on baseline MRI of soft-tissue sarcomas: longest diameter, sum and product of diameters, and volume-which is the best measurement method to predict patients' outcomes?
期刊:La Radiologia medica
日期:2024-10-18
DOI :10.1007/s11547-024-01895-8
PURPOSE:The longest diameter (LD) is a strong prognostic factor for patients with soft-tissue sarcoma (STS). Other dimensional assessments, such as the sum of diameters (SoD), product of diameters (PoD), and volume (3D-COG - proposed by the Children Oncology Group), can be rapidly performed; however, their prognostic values have never been compared to LD. Our goal was to investigate their performance in improving patients' prognostication for STS of the lower limbs. METHODS:All consecutive adults managed with curative intent at our sarcoma reference center for a newly diagnosed STS of the lower limbs between 2000 and 2017, with pre-treatment MRI, were included in this retrospective study. Multivariable Cox regression models were trained to predict metastasis-free survival (MFS) in a Training cohort of 66.7% patients based on LD, PoD, SoD, or 3D-COG (and systematically including age, histologic grade, histotype, radiotherapy, chemotherapy, and surgical margins as covariables). The models were then compared on a validation cohort of 33.3% patients using concordance indices (c-index). The same approach was applied for overall survival (OS) and local relapse-free survival (LFS). Measurement reproducibility among three readers was evaluated with an intraclass correlation coefficient (ICC). RESULTS:382 patients were included in the survival modeling (72/253 [28.5%] metastatic relapses in Training and 36/129 [27.9%] metastatic relapses in Validation). Higher dimensions were associated with lower MFS (multivariable hazard ratio [HR] = 2.44 and P = 0.0018 for LD; HR = 1.88 and P = 0.0009 for PoD, HR = 1.52 and P = 0.0041 for SoD; and HR = 1.08 and P = 0.0195 for 3D-COG). Higher c-indices were obtained with PoD model in Training (c-index = 0.772) and Validation (c-index = 0.688), but they were not significantly higher than those obtained with LD model. None of the measurements was associated with LFS or OS. All measurements demonstrated excellent ICC (> 0.95). CONCLUSION:Regarding its simplicity and good performance, LD appeared as the best metric to incorporate in prognostic models and nomograms for MFS.
添加收藏
创建看单
引用
1区Q1影响因子: 10
英汉
86. Single-Cell RNA Sequencing of Ewing Sarcoma Tumors Demonstrates Transcriptional Heterogeneity and Clonal Evolution.
期刊:Clinical cancer research : an official journal of the American Association for Cancer Research
日期:2025-05-15
DOI :10.1158/1078-0432.CCR-24-2040
PURPOSE:Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis compared with the >70% 5-year survival of those with localized disease. Novel therapeutic approaches that can impact metastatic disease are desperately needed, as well as a deeper understanding of the heterogeneity of Ewing sarcoma tumors. EXPERIMENTAL DESIGN:In this study, we utilized single-cell RNA sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and the surrounding tumor microenvironment in a cohort of seven untreated patients with Ewing sarcoma, as well as in circulating tumor cells (CTC). A potential CTC therapeutic target was evaluated through immunofluorescence of fixed CTCs from a separate cohort. RESULTS:Primary tumor samples demonstrate a heterogeneous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and Ewing sarcoma gene targets, which were found to correlate with overall survival. Copy-number analysis identified subclonal evolution within patients prior to treatment. Analyses of the immune microenvironment reveal an immunosuppressive microenvironment with complex intercellular communication among the tumor and immune cells. Single-cell RNA sequencing and immunofluorescence of CTCs at the time of diagnosis identified TSPAN8 as a potential therapeutic target. CONCLUSIONS:Ewing sarcoma tumors demonstrate significant transcriptional heterogeneity as well as a complex immunosuppressive microenvironment. This work evaluates several proposed targets that warrant further exploration as novel therapeutic strategies.
添加收藏
创建看单
引用
2区Q1影响因子: 5.7
英汉
87. Evaluation of plasma alpha-1-antichymotrypsin as a marker for pulmonary Kaposi sarcoma.
期刊:International journal of cancer
日期:2025-01-30
DOI :10.1002/ijc.35351
Individuals with AIDS and Kaposi sarcoma (AIDS-KS) with pulmonary involvement have high-risk of poor outcomes but diagnosis of pulmonary KS in low-resource settings is difficult. We aimed to discover plasma proteins that distinguish individuals with pulmonary KS from those without pulmonary involvement. SomaScan proteomics screen measured 7288 plasma proteins in 22 cases and 17 controls selected from 181 participants with HIV-1 and cutaneous KS who underwent bronchoscopy. Cases had KS in the lower respiratory tract by bronchoscopy. Controls had no KS lesions detected by bronchoscopy. Results of the proteomics screen were confirmed by ELISA measurement of plasma alpha-1-antichymotrypsin (SERPINA3) in 18 cases and 13 controls and in an additional 162 individuals with AIDS-KS who were not included in the case-control analysis. Proteomics identified 12 plasma proteins with differential levels in controls and cases. Plasma alpha-1-antichymotrypsin (SERPINA3) complex was consistently higher in cases compared to controls in the proteomics assay. Measurement of plasma alpha-1-antichymotrypsin by ELISA confirmed higher levels in cases (median 399.4, IQR 95.77-766.4 μg/ml) versus controls (median 39.98, IQR 31.2-170.2 μg/ml; p = .001). Plasma alpha-1-antichymotrypsin correlated with the estimated burden of pulmonary KS in the respiratory tract (r = 0.439; p = .0002) and 234 μg/ml had 51% sensitivity and 94% specificity for detection of pulmonary KS by bronchoscopy. Measurement of plasma alpha-1-antichymotrypsin has potential for identifying persons with pulmonary AIDS-KS and estimating the burden of KS in the lower respiratory tract.
添加收藏
创建看单
引用
1区Q1影响因子: 12.5
跳转PDF
登录
英汉
88. Chromoplexy Is a Frequent Early Clonal Event in EWSR1-Rearranged Round Cell Sarcomas That Can Be Detected Using Clinically Validated Targeted Sequencing Panels.
期刊:Cancer research
日期:2024-05-02
DOI :10.1158/0008-5472.CAN-23-2573
Chromoplexy is a phenomenon defined by large-scale chromosomal chained rearrangements. A previous study observed chromoplectic events in a subset of Ewing sarcomas (ES), which was linked to an increased relapse rate. Chromoplexy analysis could potentially facilitate patient risk stratification, particularly if it could be detected with clinically applied targeted next-generation sequencing (NGS) panels. Using DELLY, a structural variant (SV) calling algorithm that is part of the MSK-IMPACT pipeline, we characterized the spectrum of SVs in EWSR1-fused round cell sarcomas, including 173 ES and 104 desmoplastic small round cell tumors (DSRCT), to detect chromoplexy and evaluate its association with clinical and genomic features. Chromoplectic events were detected in 31% of the ES cases and 19% of the DSRCT cases. EWSR1 involvement accounted for 76% to 93% of these events, being rearranged with diverse noncanonical gene partners across the genome, involving mainly translocations but also intrachromosomal deletions and inversions. A major breakpoint cluster was located on EWSR1 exons 8-13. In a subset of cases, the SVs disrupted adjacent loci, forming deletion bridges. Longitudinal sequencing and breakpoint allele fraction analysis showed that chromoplexy is an early event that remains detectable throughout disease progression and likely develops simultaneously with the driver fusion. The presence of chromoplexy was validated in an external ES patient cohort with whole exome sequencing. Chromoplexy was significantly more likely to be present in cases that were metastatic at presentation. Together, this study identifies chromoplexy as a frequent genomic alteration in diverse EWSR1-rearranged tumors that can be captured by targeted NGS panels. SIGNIFICANCE:Chromoplexy is detectable using targeted NGS in a substantial portion of EWSR1-rearranged round cell sarcomas as an early and persistent clonal event, expanding the genomic complexity of fusion-associated sarcomas.
添加收藏
创建看单
引用
1区Q1影响因子: 14.7
跳转PDF
登录
英汉
89. The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma.
期刊:Nature communications
日期:2025-02-02
DOI :10.1038/s41467-025-56632-0
Ewing sarcoma (ES) is an aggressive bone cancer driven by the oncogenic fusion-protein EWSR1::FLI1, which is not present in normal cells and is therefore an attractive therapeutic target. However, as a transcription factor, EWSR1::FLI1 is considered undruggable. Factors that promote EWSR1::FLI1 expression, and thus whose inhibition would reduce EWSR1::FLI1 protein levels and function, are potential drug targets. Here, using genome-scale CRISPR/Cas9 knockout screening, we identify C1GALT1, a galactosyltransferase required for the biosynthesis of many O-glycoproteins, as a factor that promotes EWSR1::FLI1 expression. We show that C1GALT1 acts by O-glycosylating the pivotal Hedgehog (Hh) signaling component Smoothened (SMO), thereby stabilizing SMO and stimulating the Hh pathway, which we find directly activates EWSR1::FLI1 transcription. Itraconazole, an FDA-approved anti-fungal agent that is known to inhibit C1GALT1, reduces EWSR1::FLI1 levels in ES cell lines and suppresses growth of ES xenografts in mice. Our study reveals a therapeutically targetable mechanism that promotes EWSR1::FLI1 expression and ES tumor growth.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
90. Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma.
期刊:Molecular cancer
日期:2024-11-15
DOI :10.1186/s12943-024-02168-8
Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
91. Fertility-sparing treatment and follow-up in patients with cervical cancer, ovarian cancer, and borderline ovarian tumours: guidelines from ESGO, ESHRE, and ESGE.
期刊:The Lancet. Oncology
日期:2024-08-28
DOI :10.1016/S1470-2045(24)00262-6
The European Society of Gynaecological Oncology, the European Society of Human Reproduction and Embryology, and the European Society for Gynaecological Endoscopy jointly developed clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing strategies and follow-up of patients with cervical cancers, ovarian cancers, and borderline ovarian tumours. The developmental process of these guidelines is based on a systematic literature review and critical appraisal involving an international multidisciplinary development group consisting of 25 experts from relevant disciplines (ie, gynaecological oncology, oncofertility, reproductive surgery, endoscopy, imaging, conservative surgery, medical oncology, and histopathology). Before publication, the guidelines were reviewed by 121 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover oncological aspects of fertility-sparing strategies during the initial management, optimisation of fertility results and infertility management, and the patient's desire for future pregnancy and beyond.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
打开PDF
登录
英汉
92. The periosteum provides a stromal defence against cancer invasion into the bone.
期刊:Nature
日期:2024-08-21
DOI :10.1038/s41586-024-07822-1
The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
打开PDF
登录
英汉
93. Spatiotemporal Mapping of Lymphatic Metastases in Gastric Cancer Using Tumor-Trackable and Enzyme-Activatable Near-Infrared Fluorescent Nanoprobes.
期刊:ACS nano
日期:2024-12-16
DOI :10.1021/acsnano.4c12915
Sentinel lymph node biopsy holds significant importance in cancer management, yet the challenge persists in early detection and precise resection of metastasis lymph nodes (LNs) due to the absence of specific and sensitive optical probes. This study reports metastatic LN reporters (MLRs) with an activatable optical output for accurate spatiotemporal mapping of lymphatic metastases in gastric cancer. MLRs are self-assembled entities incorporating mixed amphiphiles with a lipophilic tail and a tumor-targeting ligand or a fluorescent moiety that is caged with a switch cleavable by tumor-specific β-galactosidase (β-Gal). After draining into LNs, MLRs selectively activate their near-infrared fluorescence in the presence of spreading tumor cells. In orthotopic gastric cancer mouse models, the representative reporter MLR1 distinguishes macro/micrometastatic LNs from benign LNs and enables early detection of skip LNs metastasis patterns in a spatial-dependent manner. Such an active sensing mechanism provides a high level of sensitivity and specificity comparable to those of flow cytometry analysis. In surgically resected patient specimens, MLR1 differentiates cancerous tissues and metastatic LNs from normal tissues and benign LNs within 1 h. This study thus presents NIRF nanoprobes that permit facile detection of LN metastases in GC patient samples and highlights a generic translatable nanoprobe design for understanding metastatic progression.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
94. Bioorthogonal Chemistry-Guided Inhalable Nanoprodrug to Circumvent Cisplatin Resistance in Orthotopic Nonsmall Cell Lung Cancer.
期刊:ACS nano
日期:2024-11-09
DOI :10.1021/acsnano.4c10947
Pulmonary delivery of anticancer therapeutics has shown encouraging performance in treating nonsmall cell lung cancer (NSCLC), which is characterized by high aggressiveness and poor prognosis. Cisplatin, a key member of the family of DNA alkylating agents, is extensively employed during NSCLC therapy. However, the development of chemoresistance and the occurrence of side effects severely impede the long-term application of cisplatin-based chemotherapies. Herein, we propose a meaningful strategy to precisely treat cisplatin-resistant NSCLC based on the combination of bioorthogonal chemistry with an inhalation approach. Ethacraplatin (EA-Pt), a platinum prodrug (IV), was synthesized and encapsulated in nitric oxide (NO)-containing micelles to overcome cisplatin chemoresistance. By further modifying bioorthogonal molecules in this nanoplatform (EA-Pt@M), an improved targeting performance toward pulmonary cancerous regions is achieved after prelabeling with azide via inhalation. Upon entering acidic cancer cells, EA-Pt is swiftly released due to the pH sensitivity of bioorthogonal micelles, which enables its bifunctions to inhibit glutathione -transferase activity and deplete intracellular glutathione, eventually reversing cisplatin resistance. Moreover, the released NO also improves the overall therapeutic outcome against NSCLC. Consequently, inhalable EA-Pt@M prelabeled by azide effectively inhibits the progression of cisplatin-resistant orthotopic NSCLC, offering a feasible nanostrategy to expand the treatment options for NSCLC.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
跳转PDF
登录
英汉
95. Randomized Comparison of Magnetic Resonance Imaging Versus Transurethral Resection for Staging New Bladder Cancers: Results From the Prospective BladderPath Trial.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2025-01-14
DOI :10.1200/JCO.23.02398
PURPOSE:Transurethral resection of bladder tumor (TURBT) is the initial staging procedure for new bladder cancers (BCs). For muscle-invasive bladder cancers (MIBCs), TURBT may delay definitive treatment. We investigated whether definitive treatment can be expedited for MIBC using flexible cystoscopic biopsy and multiparametric magnetic resonance imaging (mpMRI) for initial staging. PATIENTS AND METHODS:We conducted a prospective open-label, randomized study conducted within 17 UK hospitals (registered as ISRCTN 35296862). Participants with suspected new BC were randomly assigned 1:1 to TURBT-staged or mpMRI-staged care, with minimization factors of sex, age, and clinician visual assessment of stage. Blinding was not possible. Patients unable/unwilling to undergo mpMRI or with previous BC were ineligible. The study had two stages with separate primary outcomes of feasibility and time to correct treatment (TTCT) for MIBC, respectively. RESULTS:Between May 31, 2018, and December 31, 2021, 638 patients were screened, and 143 participants randomly assigned to TURBT (n = 72; 55 males, 15 MIBCs) or initial mpMRI (n = 71; 53 males, 14 MIBCs). For feasibility, 36 of 39 (92% [95% CI, 79 to 98]) participants with suspected MIBC underwent mpMRI. The median TTCT for participants with MIBC was significantly shorter with initial mpMRI (n = 12, 53 days [95% CI, 20 to 89] n = 14, 98 days [95% CI, 72 to 125] for TURBT, log-rank .02). There was no detriment for participants with non-MIBC (median TTCT: n = 30, 17 days [95% CI, 8 to 25] for mpMRI n = 28, 14 days [95% CI, 10 to 29] for TURBT, log-rank = .67). No serious adverse events were reported. CONCLUSION:The mpMRI-directed pathway led to a 45-day reduction in TTCT for MIBC. Incorporating mpMRI ahead of TURBT into the standard pathway was beneficial for all patients with suspected MIBC.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
96. Wip1 phosphatase activator QGC-8-52 specifically sensitizes p53-negative cancer cells to chemotherapy while protecting normal cells.
期刊:Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
日期:2024-12-24
DOI :10.1016/j.drup.2024.101196
PP2C serine-threonine phosphatase Wip1 plays an important role in normal tissue homeostasis, stress signaling and pathogenesis of various human diseases. It is an attractive drug target for cancer treatment and inhibition of its expression or activity constitute a novel therapeutic intervention strategy to prevent the development of various cancers. However, previous strategies for Wip1 suppression may be ineffective in cancers lacking p53. Here, we have characterized the activity of a novel Wip1 phosphatase activator, QGC-8-52, in preclinical models of breast malignancies. QGC-8-52 significantly sensitizes the cancer cell lines with p53 deletion to chemotherapeutic agents. This effect was mediated by the Wip1-FOXO3a interaction and subsequent dephosphorylation of Thr487 that resulted, in response to anticancer treatment, in enhancing the transcription activity of FOXO3a on the proapoptotic TRAIL gene. The sensitizing effect of Wip1 activation on chemotherapeutic drugs only targeted cancer cells lacking p53. The activation of Wip1 in normal cells provided protection from anticancer drug-induced apoptosis by reducing the strength of upstream signaling to p53. Therefore, during the treatment of anticancer drugs, the activated Wip1 phosphatase boosts the apoptosis of p53-negative tumors and protects normal tissues. Our findings may represent an effective and safe therapeutic strategy for cancers with p53 deletion.
添加收藏
创建看单
引用
1区Q1影响因子: 29.7
跳转PDF
登录
英汉
97. The Germline and Somatic Origins of Prostate Cancer Heterogeneity.
期刊:Cancer discovery
日期:2025-05-02
DOI :10.1158/2159-8290.CD-23-0882
SIGNIFICANCE:This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.
添加收藏
创建看单
引用
1区Q1影响因子: 20.1
跳转PDF
登录
英汉
98. Cancer situation in China: an analysis based on the global epidemiological data released in 2024.
期刊:Cancer communications (London, England)
日期:2024-12-10
DOI :10.1002/cac2.12627
BACKGROUND:Cancer remains a major cause of mortality and a significant economic burden in China. Exploring the disparities in cancer patterns and control strategies between China and developed countries may offer valuable insights for policy formulation and enhance cancer management efforts. This study examined the incidence, mortality, and disability-adjusted life year (DALY) burden of cancer in China, and compared these metrics with those observed in the United States (US) and the United Kingdom (UK). METHODS:Data on cancer incidence, mortality, and DALYs for China, the US, and the UK were sourced from the GLOBOCAN 2022 online database and the Global Burden of Disease 2021 study (GBD 2021). We utilized Joinpoint regression models to analyze trends in cancer incidence and mortality across these countries, calculating annual percent changes (APCs) and determining the optimal joinpoints. RESULTS:In 2022, China recorded around 4,824,703 new cancer cases and 2,574,176 cancer-related deaths, contributing to 71,037,170 DALYs. China exhibited a lower cancer incidence rate compared to the US and the UK. Although cancer-related mortality in China is slightly lower than that in the UK, it is significantly higher than that in the US. Additionally, China experienced significantly higher DALY rates compared to both the US and UK. The cancer landscape in China was also undergoing significant changes, with a rapid rise in the incidence and burden of lung, colorectal, breast, cervical, and prostate cancers. Meanwhile, the incidence and burden of stomach cancer continued to decline. Although the incidence of liver and esophageal cancers was decreasing, the burden of liver cancer was increasing, while the burden of esophageal cancer remained largely unchanged. CONCLUSIONS:The cancer profile of China is shifting from that of a developing country to one more typical of a developed country. The ongoing population aging and the rise in unhealthy lifestyles are expected to further escalate the cancer burden in China. Consequently, it is crucial for Chinese authorities to revise the national cancer control program, drawing on successful strategies from developed countries, while also accounting for the regional diversity in cancer types across China.
添加收藏
创建看单
引用
1区Q1影响因子: 29.5
跳转PDF
登录
英汉
99. Noncoding RNA-encoded peptides in cancer: biological functions, posttranslational modifications and therapeutic potential.
期刊:Journal of hematology & oncology
日期:2025-02-19
DOI :10.1186/s13045-025-01671-9
In the present era, noncoding RNAs (ncRNAs) have become a subject of considerable scientific interest, with peptides encoded by ncRNAs representing a particularly promising avenue of investigation. The identification of ncRNA-encoded peptides in human cancers is increasing. These peptides regulate cancer progression through multiple molecular mechanisms. Here, we delineate the patterns of diverse ncRNA-encoded peptides and provide a synopsis of the methodologies employed for the identification of ncRNAs that possess the capacity to encode these peptides. Furthermore, we discuss the impacts of ncRNA-encoded peptides on the biological behavior of cancer cells and the underlying molecular mechanisms. In conclusion, we describe the prospects of ncRNA-encoded peptides in cancer and the challenges that need to be overcome.
添加收藏
创建看单
引用
1区Q1影响因子: 19.9
跳转PDF
登录
英汉
100. Variability and social patterning of cancer mortality in 343 Latin American cities: an ecological study.
期刊:The Lancet. Global health
日期:2025-02-01
DOI :10.1016/S2214-109X(24)00446-7
BACKGROUND:Understanding between-city variations in cancer mortality is crucial to inform national and subnational cancer prevention strategies. However, studies at the city level in Latin America are scarce. As part of the Salud Urbana en América Latina (SALURBAL) project, we aimed to describe the variability in cancer mortality rates across 343 cities in nine Latin American countries and the associations of these rates with city-level socioeconomic development. METHODS:This ecological study used data from cities in Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Guatemala, Mexico, and Panama. Vital registration and population data from Jan 1, 2015 to Dec 31, 2019 were used to estimate sex-specific and age-standardised cancer mortality rates for each city, overall and for seven cancer sites (breast, lung, colorectal, stomach, liver, prostate, and cervical), and the associations of these rates with city-level socioeconomic development. FINDINGS:We found wide variability in cancer mortality by city (overall age-adjusted cancer mortality rates varied by almost three times), sex, and cancer site. Variability between cities within the same country was highest for cervical and prostate cancer. The most common causes of cancer deaths were breast cancer (305 cities) for females and prostate cancer (167 cities) and lung cancer (132 cities) for males. Liver and cervical cancer were the primary cause of cancer mortality in fewer than ten cities each, most of which were in Guatemala and Mexico. Lower city-level socioeconomic development was associated with higher mortality from liver, stomach, cervical, and prostate cancers and lower mortality from breast, colorectal, and lung cancers, with variations by sex. INTERPRETATION:We found considerable heterogeneity in cancer mortality between cities, geographical patterning, and associations between cancer mortality rates and socioeconomic development. Our results highlight the need to consider city contexts when planning interventions to reduce cancer mortality and when guiding future cancer prevention and control efforts in urban areas within the region. FUNDING:Wellcome Trust. TRANSLATIONS:For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.
添加收藏
创建看单
引用
2区Q1影响因子: 6.3
跳转PDF
登录
英汉
101. Asiaticoside-nitric oxide synergistically accelerate diabetic wound healing by regulating key metabolites and SRC/STAT3 signaling.
期刊:Burns & trauma
日期:2025-03-10
DOI :10.1093/burnst/tkaf009
Background:Diabetic wounds pose significant clinical challenges due to impaired healing processes, often resulting in chronic, nonhealing ulcers. Asiaticoside (AC), a natural triterpene derivative from , has demonstrated notable anti-inflammatory and wound-healing properties. However, the synergistic effects of nitric oxide (NO)-a recognized promoter of wound healing-combined with AC in treating diabetic wounds remain inadequately explored. Methods:Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was utilized to identify differential metabolites and dysregulated metabolic pathways associated with diabetic wounds. Molecular docking analyses were conducted to confirm the binding affinity of AC to key therapeutic targets. The effects of asiaticoside-nitric oxide hydrogel (ACNO) on gene and protein expression were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. experiments using sarcoma (SRC) agonists and inhibitors were performed to investigate the impact of ACNO therapy on the expression of SRC, STAT3, and other proteins in HaCaT cells. Results:Metabolomic profiling revealed that diabetic wounds in mice exhibited marked metabolic dysregulation, which was attenuated by ACNO treatment. Key metabolites modulated by ACNO included mandelic acid, lactic acid, and 3-hydroxyisovaleric acid. The primary metabolic pathways involved were methyl histidine metabolism and the malate-aspartate shuttle. Immunofluorescence staining confirmed that ACNO therapy enhanced angiogenesis, promoted cellular proliferation, and facilitated diabetic wound closure. RT-qPCR data demonstrated that ACNO regulated the transcription of critical genes (, , , and ). Notably, ACNO attenuated SRC/STAT3 pathway activation while concurrently upregulating EGFR and VEGFA expression. Conclusions:These findings emphasize the therapeutic potential of ACNO hydrogel in diabetic wound healing through the modulation of metabolic pathways and the SRC/STAT3 signaling axis. By correlating altered metabolites with molecular targets, this study elucidates the pharmacodynamic foundation for ACNO's preclinical application and provides valuable insights into the development of targeted therapies for diabetic wound management.
添加收藏
创建看单
引用
1区Q1影响因子: 5.5
跳转PDF
登录
英汉
102. Unidirectional recruitment between MeCP2 and KSHV-encoded LANA revealed by CRISPR/Cas9 recruitment assay.
期刊:PLoS pathogens
日期:2025-03-10
DOI :10.1371/journal.ppat.1012972
Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) is associated with several human malignancies. During latency, the viral genomes reside in the nucleus of infected cells as large non-integrated plasmids, known as episomes. To ensure episome maintenance, the latency protein LANA tethers the viral episomes to the cell chromosomes during cell division. Directional recruitment of protein complexes is critical for the proper function of many nuclear processes. To test for recruitment directionality between LANA and cellular proteins, we directed LANA via catalytically inactive Cas9 (dCas9) to a repeat sequence to obtain easily detectable dots. Then, the recruitment of nuclear proteins to these dots can be evaluated. We termed this assay CRISPR-PITA for Protein Interaction and Telomere Recruitment Assay. Using this protein recruitment assay, we found that LANA recruits its known interactors ORC2 and SIN3A. Interestingly, LANA was unable to recruit MeCP2, but MeCP2 recruited LANA. Both LANA and histone deacetylase 1 (HDAC1) interact with the transcriptional-repression domain (TRD) and the methyl-CpG-binding domain (MBD) of MeCP2. Similar to LANA, HDAC1 was unable to recruit MeCP2. While heterochromatin protein 1 (HP1), which interacts with the N-terminal of MeCP2, can recruit MeCP2. We propose that available interacting domains force this recruitment directionality. We hypothesized that the tandem repeats in the SunTag may force MeCP2 dimerization and mimic the form of DNA-bound MeCP2. Indeed, providing only the tandem epitopes of SunTag allows LANA to recruit MeCP2 in infected cells. Therefore, CRISPR-PITA revealed the rules of unidirectional recruitment and allowed us to break this directionality.
添加收藏
创建看单
引用
1区Q1影响因子: 44.7
英汉
103. To target, to escape, perchance to cure: Borrowing a page from cancer's playbook, scientists learn to evade their own therapies.
期刊:Science (New York, N.Y.)
日期:2024-11-14
DOI :10.1126/science.adt9029
Borrowing a page from cancer's playbook, scientists learn to evade their own therapies.
添加收藏
创建看单
引用
1区Q1影响因子: 11
英汉
104. Rapid improvements in Kaposi sarcoma with metformin: a report of two cases.
期刊:The British journal of dermatology
日期:2025-03-11
DOI :10.1093/bjd/ljaf090
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
跳转PDF
登录
英汉
105. YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells.
期刊:Cell reports
日期:2025-03-12
DOI :10.1016/j.celrep.2025.115381
Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF)-1 is an autocrine growth factor for EwS, but only 10% of patients respond to IGF-1 receptor (IGF-1R) blockade. Although EwS is presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but in skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprograms limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identify a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reverses the transformed phenotype of EWS::FLI1-expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients.
添加收藏
创建看单
引用
1区Q1影响因子: 8.1
跳转PDF
登录
英汉
106. Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity.
期刊:Cell death & disease
日期:2025-03-12
DOI :10.1038/s41419-025-07467-6
The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.
添加收藏
创建看单
引用
1区Q1影响因子: 12.5
英汉
107. Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response.
期刊:Cancer research
日期:2025-03-14
DOI :10.1158/0008-5472.CAN-24-3281
Radiotherapy is an integral component in the treatment of many types of cancer, with approximately half of patients with cancer receiving radiotherapy. Systemic therapy applies pressure that can select for resistant tumor subpopulations, underscoring the importance of understanding how radiation impacts tumor evolution to improve treatment outcomes. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPSs displayed initial linear evolution, followed by subsequent branching evolution with distinct mutational processes during early and late development. Metrics of genetic divergence between regions provided evidence of strong selection pressures during UPS development that further increased during radiotherapy. Subclone abundance changed after radiotherapy with subclone contraction tied to alterations in calcium signaling, and inhibiting calcium transporters radiosensitized sarcoma cells. Finally, circulating tumor DNA analysis accurately measured subclone abundance and enabled noninvasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPSs and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy. Significance: Radiotherapy mediates tumor evolution by leading to the expansion of resistant subclonal cancer cell populations, indicating that developing approaches to target resistant subclones will be crucial to improve radiotherapy response.
添加收藏
创建看单
引用
1区Q1影响因子: 6.1
跳转PDF
登录
英汉
108. Health literacy and all-cause mortality among cancer patients.
期刊:Cancer
日期:2025-03-15
DOI :10.1002/cncr.35794
BACKGROUND:The association between health literacy and all-cause mortality among cancer patients remains unclear. METHODS:This is a retrospective cohort study of 9603 patients diagnosed with prostate, lung, breast, renal, colorectal, brain, head and neck, bladder, pancreatic, liver, sarcoma, and gastric cancers who were screened for health literacy between 2008 and 2018, using the Brief Health Literacy Screen (BHLS). Higher scores (range, 3-15) indicate higher health literacy. The association between all-cause mortality and health literacy was estimated using multivariable Cox proportional hazards models. RESULTS:A total of 8608 (89%) patients were non-Hispanic White. The median follow-up was 3.1 years. Patients with a BHLS score of 15 had a median survival improvement of 9.4 months (95% confidence interval [CI], 6.0-13.2 months) compared to those with a score of 9. Lower BHLS scores (9 vs. 15) were associated with higher mortality in stages II (adjusted hazard ratio [aHR], 2.6 [95% CI, 1.5-5.1]) and III (aHR 2.9 [95% CI, 1.4-6.0]) prostate cancer; stages I (aHR 1.7 [95% CI, 1.1-2.5]) and IV (aHR, 1.6 [95% CI, 1.2-2.1]) lung cancer; stage I colorectal cancer (aHR, 2.2 [95% CI, 1.3-4.7]); stage I renal cancer (aHR, 1.8 [95% CI, 1.1-3.4]); stages I (aHR, 2.6 [95% CI, 1.3-7.1]) and IV (aHR, 1.7 [95% CI, 1.2-2.7]) head and neck cancer; stage II bladder cancer (aHR, 1.6 [95% CI, 1.0-2.8]); stage I liver cancer (aHR, 4.1 [95% CI, 1.9-9.3]); and all stages of breast cancer. CONCLUSIONS:Lower health literacy was associated with higher all-cause mortality among patients with 12 different types of cancer, varying by cancer type and stage.
添加收藏
创建看单
引用
1区Q1影响因子: 5.2
英汉
109. Thermal Protection Techniques for Image-guided Musculoskeletal Ablation.
期刊:Radiographics : a review publication of the Radiological Society of North America, Inc
日期:2025-04-01
DOI :10.1148/rg.240078
Percutaneous image-guided thermal ablation has gained wide acceptance among physicians for the treatment of benign and malignant tumors of the musculoskeletal system. Increasing evidence to support the efficacy of thermal ablation techniques in primary and adjuvant treatment of soft-tissue sarcomas, treatment of oligometastatic disease to bone and soft tissue, and metastatic pain palliation has positioned interventional oncology alongside surgery, systemic therapies, and radiation therapy as the fourth pillar of modern comprehensive cancer care. Despite the expanding indications and increasing use in clinical practice, thermal ablation carries a significant risk of injury to the adjacent vulnerable structures, predominantly the skin, bowel, and neural structures. Knowledge of the mechanism of action of each thermal ablation modality informs the physician of the attendant risks associated with a particular modality. Thermal ablation mechanisms can be divided into hypothermic (cryoablation) and hyperthermic (radiofrequency ablation, microwave ablation, high-intensity focused US, or laser). Active thermal protection techniques include hydrodissection, pneumodissection, direct skin thermal protection, and physical displacement techniques. Passive thermal protection techniques include temperature monitoring, biofeedback, and neurophysiologic monitoring. The authors provide an overview of the mechanism of action of the most commonly used thermal ablation modalities, review the thermal injury risks associated with these modalities, and introduce the active and passive thermal protective techniques critical to safe and effective musculoskeletal ablative therapy. RSNA, 2025 See the invited commentary by Tomasian and Jennings in this issue.
添加收藏
创建看单
引用
1区Q1影响因子: 31.7
跳转PDF
登录
英汉
110. The transcriptomic architecture of common cancers reflects synthetic lethal interactions.
期刊:Nature genetics
日期:2025-03-03
DOI :10.1038/s41588-025-02108-2
To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression of BRCA1/2 synthetic lethal genes correlates with clinical outcome. Synthetic lethal genes that exhibit transcriptomic buffering also represent more robust synthetic lethal effects. These observations have implications for understanding how tumor cells tolerate TSG loss, in part explain transcriptomic architectures in cancer and provide insight into target selection.
添加收藏
创建看单
引用
1区Q1影响因子: 28.4
跳转PDF
登录
英汉
111. Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.
期刊:Annual review of pathology
日期:2025-01-02
DOI :10.1146/annurev-pathmechdis-111523-023420
Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting , , , , and are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including / associated predisposition, deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.
添加收藏
创建看单
引用
1区Q1影响因子: 21
英汉
112. Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.
期刊:Blood
日期:2024-01-11
DOI :10.1182/blood.2023022345
ABSTRACT:Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
113. Traditional Chinese medicine in treating upper digestive tract cancers.
期刊:Molecular cancer
日期:2024-11-08
DOI :10.1186/s12943-024-02149-x
Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
114. Pulmonary neuroendocrine neoplasms: the molecular landscape, therapeutic challenges, and diagnosis and management strategies.
期刊:The Lancet. Oncology
日期:2025-01-01
DOI :10.1016/S1470-2045(24)00374-7
Lung neuroendocrine neoplasms are a group of diverse, heterogeneous tumours that range from well-differentiated, low-grade neuroendocrine tumours-such as typical and atypical carcinoids-to high-grade, poorly differentiated aggressive malignancies, such as large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). While the incidence of SCLC has decreased, the worldwide incidence of other pulmonary neuroendocrine neoplasms has been increasing over the past decades. In addition to the standard histopathological classification of lung neuroendocrine neoplasms, the introduction of molecular and sequencing techniques has led to new advances in understanding the biology of these diseases and might influence future classifications and staging that can subsequently improve management guidelines in the adjuvant or metastatic settings. Due to the rarity of neuroendocrine neoplasms, there is a paucity of prospective studies that focus on the lungs, especially in rare, well-differentiated carcinoids and LCNECs. In contrast with the success of targeted therapies in non-small-cell lung cancer (NSCLC), high-grade neuroendocrine carcinomas of the lung often only have a few specific targetable gene alterations. Optimal therapy for LCNECs is not well defined and treatment recommendations are based on extrapolating guidelines for the management of patients with SCLC and NSCLC. This Review explores the epidemiology, diagnosis, and staging of lung neuroendocrine neoplasms to date. In addition, we focus on the evolving molecular landscape and biomarkers, ranging from tumour phenotypes to functional imaging studies and novel molecular biomarkers. We outline the various clinical outcomes, challenges, the treatment landscape, ongoing clinical trials, and future directions.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
115. Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2024-10-02
DOI :10.1200/JCO.23.01430
PURPOSE:Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. METHODS:We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. RESULTS:In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine (MIBG) treatment. Survivors treated with MIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without MIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). CONCLUSION:Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. MIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.
添加收藏
创建看单
引用
1区Q1影响因子: 40.8
跳转PDF
登录
英汉
116. Digestive cancers: mechanisms, therapeutics and management.
期刊:Signal transduction and targeted therapy
日期:2025-01-15
DOI :10.1038/s41392-024-02097-4
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
Aggressive tumors pose ultra-challenges to drug resistance. Anti-cancer treatments are often unsuccessful, and single-cell technologies to rein drug resistance mechanisms are still fruitless. The National Cancer Institute defines aggressive cancers at the tissue level, describing them as those that spread rapidly, despite severe treatment. At the molecular, foundational level, the quantitative biophysics discipline defines aggressive cancers as harboring a large number of (overexpressed, or mutated) crucial signaling proteins in major proliferation pathways populating their active conformations, primed for their signal transduction roles. This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels, focusing on the differences between highly aggressive cancers and the more treatable ones. It showcases aggressive tumors as harboring massive, cancer-promoting, catalysis-primed oncogenic proteins, especially through certain overexpression scenarios, as predisposed aggressive tumor candidates. Our examples narrate strong activation of ERK1/2, and other oncogenic proteins, through malfunctioning chromatin and crosslinked signaling, and how they activate multiple proliferation pathways. They show the increased cancer heterogeneity, plasticity, and drug resistance. Our review formulates the principles underlying cancer aggressiveness on the molecular level, discusses scenarios, and describes drug regimen (single drugs and drug combinations) for PDAC, NSCLC, CRC, HCC, breast and prostate cancers, glioblastoma, neuroblastoma, and leukemia as examples. All show overexpression scenarios of master transcription factors, transcription factors with gene fusions, copy number alterations, dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors, as well as high mutation loads of vital upstream signaling regulators, such as EGFR, c-MET, and K-Ras, befitting these principles.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
跳转PDF
登录
英汉
118. Mechanisms that clear mutations drive field cancerization in mammary tissue.
期刊:Nature
日期:2024-09-04
DOI :10.1038/s41586-024-07882-3
Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1;Trp53 cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.
添加收藏
创建看单
引用
1区Q1影响因子: 25.3
英汉
119. T-cell Engagers in Prostate Cancer.
期刊:European urology
日期:2025-03-11
DOI :10.1016/j.eururo.2025.02.001
Owing to the "cold" tumor immune microenvironment of prostate cancer, immune-targeting agents have shown limited efficacy in patients with advanced prostate cancer, highlighting the need for new therapies with novel mechanisms of action. In this context, T-cell engagers (TCEs), which induce T-cell-mediated killing of cancer cells by binding the CD3 receptor on T cells and a specific tumor antigen expressed on malignant cells, represent a promising therapeutic option. Multiple studies have explored the use of TCEs in previously treated patients with metastatic castration-resistant prostate cancer, and several ongoing trials are currently assessing novel TCEs either as single agents or in combinatorial regimens with molecules with a distinct mechanism of action (eg, androgen receptor pathway inhibitors and other immune-targeting agents). Although TCEs have shown promising antitumor activity with prostate-specific antigen and radiographic responses, they still face considerable challenges that prevent their implementation into clinical practice. These include their immunogenicity and the development of antidrug antibodies, which could impact their serum drug exposure, as well as their toxicity profile involving cytokine release syndrome and other immune-related adverse events. To improve their efficacy and pending the results of ongoing trials, there could be a role for combinatorial regimens, administration in earlier lines of therapy, and biomarker-driven selection.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
打开PDF
登录
英汉
120. Reprogramming of Thyroid Cancer Metabolism: from Mechanism to Therapeutic Strategy.
期刊:Molecular cancer
日期:2025-03-11
DOI :10.1186/s12943-025-02263-4
Thyroid cancer as one of the most prevalent malignancies of endocrine system, has raised public concern and more research on its mechanism and treatment. And metabolism-based therapies have advanced rapidly, for the exclusive metabolic profiling of thyroid cancer. In thyroid cancer cells, plenty of metabolic pathways are reprogrammed to accommodate tumor microenvironment. In this review, we initiatively summarize recent progress in the full-scale thyroid cancer metabolic rewiring and the interconnection of various metabolites. We also discuss the efficacy and prospect of metabolic targeted detection as well as therapy. Comprehending metabolic mechanism and characteristics of thyroid cancer roundly will be highly beneficial to managing individual patients.
添加收藏
创建看单
引用
1区Q1影响因子: 15.7
英汉
121. Hormone Receptor Status of Second Breast Cancers in Women With Triple-Negative Breast Cancer.
期刊:JAMA surgery
日期:2025-05-01
DOI :10.1001/jamasurg.2025.0100
添加收藏
创建看单
引用
1区Q1影响因子: 15.7
英汉
122. Prognostic Impact of Fluorescent Lymphography on Gastric Cancer After Neoadjuvant Chemotherapy.
期刊:JAMA surgery
日期:2025-05-01
DOI :10.1001/jamasurg.2025.0108
Importance:Indocyanine green (ICG)-guided lymphadenectomy has been increasingly used to treat gastric cancer. However, its oncologic impact remains unclear. Objective:To investigate the effect of ICG tracing on long-term outcomes in patients diagnosed with locally advanced gastric cancer undergoing neoadjuvant chemotherapy (NAC) followed by laparoscopic radical gastrectomy. Design, Settings, and Participants:This retrospective cohort study included patients diagnosed with cT2-4N0/+M0 gastric adenocarcinoma who underwent NAC and laparoscopic radical gastrectomy at 3 teaching hospitals in China between January 2015 and June 2021, with follow-up data examined until June 2024. Overlap weighting (OW) was used to compare outcomes between the ICG and non-ICG groups. Results were tested for robustness using propensity score matching (PSM) and instrumental variable analysis. Exposure:ICG-guided lymphadenectomy during laparoscopic gastrectomy. Main Outcomes and Measures:The primary end points were 3-year survival outcomes, including overall survival (OS) and recurrence-free survival (RFS). Results:Data from 459 patients (338 men [73.6%] and 121 women [26.4%]; mean [SD] age, 60.8 [9.9] years), of whom 119 underwent ICG-guided lymphadenectomy, were included. After OW adjustment, the ICG group exhibited a higher number of lymph nodes harvested (47.4 vs 38.3; P < .001) and better 3-year OS (78.6% vs 66.6%; P = .04) and RFS (74.0% vs 57.0%; P = .03) compared with the non-ICG group. Multivariable Cox regression analysis revealed that ICG tracing was an independent prognostic factor for both OS (hazard ratio, 0.59; 95% CI, 0.39-0.90; P = .02) and RFS (hazard ratio, 0.59; 95% CI, 0.40-0.87; P = .01), with the results remaining significant in both doubly robust and instrumental variable-adjusted models. Furthermore, in the OW-adjusted population, the OS benefit of ICG tracing was more pronounced in subgroups with ypN2/3 gastric adenocarcinoma (70.3% vs 36.2%; P = .01) and those achieving major pathological response (97.7% vs 77.6%; P = .04) (both P for interaction = .04). Similar results were obtained after adjusting for PSM. Conclusion and Relevance:In this study, ICG tracing was associated with enhanced lymphadenectomy and improved survival outcomes in patients with locally advanced gastric cancer after NAC. A prospective randomized clinical trial is needed to verify these findings.
添加收藏
创建看单
引用
1区Q1影响因子: 15.7
英汉
123. Precision Exercise Effect on Fatigue and Function in Lung Cancer Surgery: A Randomized Clinical Trial.
期刊:JAMA surgery
日期:2025-05-01
DOI :10.1001/jamasurg.2025.0130
Importance:Exercise intervention studies have shown benefits for patients with lung cancer undergoing surgery, yet most interventions to date have been resource intensive and have followed a one-size-fits-all approach. Objective:To determine whether a personalized, clinic-aligned perioperative exercise program with remote monitoring and instructions can improve physical function and fatigue among patients undergoing surgery for lung cancer. Design, Setting, and Participants:The Precision-Exercise-Prescription (PEP) randomized clinical trial is a single-center phase 3 trial. Adult patients with primary lung cancer (stages I-IIIa) or oligometastatic disease to the lung (where all disease could be removed) were assessed for eligibility and randomized to either an exercise intervention or standard care. Patients were enrolled between November 2017 and 2021, and the trial continued during the COVID-19 pandemic. Data were analyzed from November 2022 to December 2023. Interventions:The structured exercise program, personalized based on mobility scores, was a home-based exercise intervention prescribed and monitored remotely by a licensed physical therapist. The program started approximately 2 weeks before surgery and continued after surgery. Standard care included use of incentive spirometer and encouragement to exercise without a formal program. Main Outcomes and Measures:Physical function (6-minute walk test [6MWT]), the Short Physical Performance Battery, and cancer-related fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) were assessed at baseline and 2 months after surgery. Results:A total of 182 patients (92 receiving exercise intervention, 90 receiving standard care) were assessed in the intention-to-treat population. Patients had a mean (SD) age of 62.7 (13.8) years, 108 (59%) were female, and 89 (49%) had low mobility scores (Activity Measure for Post-Acute Care scores, 1-3). Physical function in the exercise group increased at 2 months after surgery (mean [SE] 6MWT at baseline, 467.9 [13.0] m; at 2 months, 482.2 [14.1] m), compared with a decrease in the standard-care group (mean [SE] 6MWT at baseline, 481.4 [11.1] m; at 2 months, 471.5 [14.0] m). Mean (SE) between-group changes in 6MWT distance for intent to treat from baseline to 2 months were 22.7 (12.7) m (P = .08), with greater effect sizes among women (mean [SE], 37.8 [17.3] m; P = .03). Similarly, women showed greater improvements in the Short Physical Performance Battery (mean [SE], 0.9 [0.4]; P = .04). Patients in the exercise group maintained stable fatigue scores at 2 months, whereas participants in the standard-care group deteriorated (mean [SD], 3.7 [1.4]; P = .009), with greater effect sizes among individuals who were younger, from rural areas, had overweight or obesity, and had primary lung cancer. Conclusions and Relevance:The PEP intervention, a personalized, clinic-aligned, and remotely monitored perioperative exercise program for patients with lung cancer undergoing surgery demonstrated improvements in physical function for women and significant improvements in fatigue scores across all groups. Trial Registration:ClinicalTrials.gov Identifier: NCT03306992.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
124. Lymphatic system is the mainstream for breast cancer dissemination and metastasis revealed by single-cell lineage tracing.
期刊:Molecular cancer
日期:2025-03-12
DOI :10.1186/s12943-025-02279-w
Cancer metastasis is the primary cause of cancer-related death, yet the forces that drive cancer cells through various steps and different routes to distinct target organs/tissues remain elusive. In this study, we applied a barcoding system based single-cell lineage tracing approach to study the metastasis rate and route of breast cancer cells and their interactions with the tumor microenvironment (TME) during metastasis. The results indicate that only a small fraction of cells, accounting for fewer than 3% of total barcodes, can intravasate from the primary site into the blood circulation, whereas more cells disseminate through the lymphatic system to different organs. Tumor cells derived from the same progenitor cell exhibit different gene expression patterns in different soils, and the cancer cell-TME communication paradigm varies significantly between primary and metastatic tumors. Furthermore, metastable cells require a prewired particular cytokine expression ability which may be specific for lymph metastasis route although the underlying mechanism requires further investigation. In summary, leveraging a single-cell lineage tracing system, we demonstrate that the crosstalk between tumor cells and the TME is the driving force controlling the preferential metastatic fate of cancer cells through the lymphatic system.
添加收藏
创建看单
引用
1区Q1影响因子: 29.7
英汉
125. RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
期刊:Cancer discovery
日期:2025-03-12
DOI :10.1158/2159-8290.CD-24-0199
Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic-acid-related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
126. Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models.
期刊:Science translational medicine
日期:2025-03-12
DOI :10.1126/scitranslmed.adp2124
The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition-activated tumor cells and matrix metallopeptidase 11 (MMP-11) cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 22.5
英汉
127. Adjuvant Chemoradiotherapy vs Radiotherapy Alone for Patients With Intermediate-Risk Cervical Cancer.
期刊:JAMA oncology
日期:2025-05-01
DOI :10.1001/jamaoncol.2025.0146
Importance:Optimal adjuvant treatment for patients with intermediate-risk cervical cancer remains controversial, and the benefit of adding chemotherapy to radiotherapy in this population is uncertain. Objective:To evaluate whether adjuvant chemoradiotherapy is associated with improved overall survival compared with radiotherapy alone in patients with intermediate-risk cervical cancer. Secondary objectives included identifying clinical factors associated with the use of chemoradiotherapy. Design, Setting, and Participants:A cohort study was conducted at Commission on Cancer-accredited centers across the US using prospectively collected data from the National Cancer Database that focused on patients with a diagnosis of 2018 International Federation of Gynecology and Obstetrics stage IB cervical carcinoma (squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma) of intermediate risk who were undergoing adjuvant radiotherapy treatment after radical hysterectomy from January 2010 through December 2020. Missing variables were multiple imputed, and propensity score matching (1:1) was performed to balance baseline characteristics. A Kaplan-Meier analysis and proportional hazard models were used to compare the hazard of death between the groups. Exposure:Adjuvant radiotherapy alone vs concurrent chemoradiotherapy. Main Outcome and Measure:The primary outcome was time to death or last follow-up. Results:A total of 1116 patients (mean [SD] age, 47 [12] years) were identified, of whom 486 (43.5%) received concurrent chemoradiotherapy. Chemotherapy was administered more frequently among those with adenocarcinoma or adenosquamous histology compared with squamous cell carcinoma (risk ratio [RR], 1.26; 95% CI, 1.10-1.44) and those with tumors larger than 4 cm (compared with tumors measuring 2-4 cm; RR, 1.31; 95% CI, 1.14-1.51). Propensity score matching yielded a cohort of 868 patients with balanced covariates. Patients who received chemoradiotherapy had similar overall survival (5- year survival, 87%) as those who received radiotherapy alone (5-year survival, 87%; hazard ratio, 0.85; 95% CI, 0.59-1.23; P = .38). There were no significant differences in survival associated with chemotherapy receipt among subgroups defined by tumor size, histology, presence of lymphovascular space invasion, surgical approach, or receipt of adjuvant brachytherapy. Conclusions and Relevance:The results of this cohort study suggest that adding chemotherapy to radiotherapy was not associated with improved overall survival for patients with intermediate-risk cervical cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 40.8
跳转PDF
登录
英汉
128. Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer.
期刊:Signal transduction and targeted therapy
日期:2025-03-14
DOI :10.1038/s41392-025-02170-6
Enhancer RNAs (eRNAs), a subclass of non-coding RNAs transcribed from enhancer regions, have emerged as critical regulators of gene expression; however, their functional roles in prostate cancer remain largely unexplored. In this study, we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues. By incorporating chromatin immunoprecipitation sequencing data, we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways. Among these, lactotransferrin-eRNA (LTFe) was markedly downregulated in prostate cancer tissues, with functional analyses revealing its tumor-suppressive role. Mechanistically, LTFe promotes the transcription of its target gene, lactotransferrin (LTF), by interacting with heterogeneous nuclear ribonucleoprotein F (HNRNPF) and facilitating enhancer-promoter chromatin interactions. Furthermore, we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport. Notably, androgen receptor (AR) signaling disrupts LTFe-associated chromatin looping, leading to ferroptosis resistance. Therapeutically, co- administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth, offering a promising strategy for castration-resistant prostate cancer. Collectively, this study provides novel insights into the mechanistic role of eRNAs in prostate cancer, highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.
添加收藏
创建看单
引用
3区Q1影响因子: 4.9
跳转PDF
登录
英汉
129. Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression.
期刊:International journal of molecular sciences
日期:2022-10-08
DOI :10.3390/ijms231911943
Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 10.1
打开PDF
登录
英汉
130. Histone lactylation drives oncogenesis by facilitating mA reader protein YTHDF2 expression in ocular melanoma.
作者:Yu Jie , Chai Peiwei , Xie Minyue , Ge Shengfang , Ruan Jing , Fan Xianqun , Jia Renbing
期刊:Genome biology
日期:2021-03-16
DOI :10.1186/s13059-021-02308-z
BACKGROUND:Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. RESULTS:Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. CONCLUSION:We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
添加收藏
创建看单
引用
1区Q1影响因子: 8.2
打开PDF
登录
英汉
131. Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.
期刊:International journal of biological sciences
日期:2022-10-24
DOI :10.7150/ijbs.75434
Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.
添加收藏
创建看单
引用
3区Q1影响因子: 4.5
英汉
132. Lactate, histone lactylation and cancer hallmarks.
期刊:Expert reviews in molecular medicine
日期:2023-01-09
DOI :10.1017/erm.2022.42
Histone lactylation, an indicator of lactate level and glycolysis, has intrinsic connections with cell metabolism that represents a novel epigenetic code affecting the fate of cells including carcinogenesis. Through delineating the relationship between histone lactylation and cancer hallmarks, we propose histone lactylation as a novel epigenetic code priming cells toward the malignant state, and advocate the importance of identifying novel therapeutic strategies or dual-targeting modalities against lactylation toward effective cancer control. This review underpins important yet less-studied area in histone lactylation, and sheds insights on its clinical impact as well as possible therapeutic tools targeting lactylation.
添加收藏
创建看单
引用
2区Q2影响因子: 4.4
跳转PDF
登录
英汉
133. Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9.
期刊:Cancer biology & therapy
日期:2024-01-16
DOI :10.1080/15384047.2024.2304161
BACKGROUND:Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism. METHODS:The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model. RESULTS:We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth. CONCLUSION:Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.
添加收藏
创建看单
引用
2区Q1影响因子: 6.1
跳转PDF
登录
英汉
134. Lactate and Lactylation: Clinical Applications of Routine Carbon Source and Novel Modification in Human Diseases.
期刊:Molecular & cellular proteomics : MCP
日期:2023-09-06
DOI :10.1016/j.mcpro.2023.100641
Cell metabolism generates numerous intermediate metabolites that could serve as feedback and feed-forward regulation substances for posttranslational modification. Lactate, a metabolic product of glycolysis, has recently been conceptualized to play a pleiotropic role in shaping cell identities through metabolic rewiring and epigenetic modifications. Lactate-derived carbons, sourced from glucose, mediate the crosstalk among glycolysis, lactate, and lactylation. Furthermore, the multiple metabolic fates of lactate make it an ideal substrate for metabolic imaging in clinical application. Several studies have identified the crucial role of protein lactylation in human diseases associated with cell fate determination, embryonic development, inflammation, neoplasm, and neuropsychiatric disorders. Herein, this review will focus on the metabolic fate of lactate-derived carbon to provide useful information for further research and therapeutic approaches in human diseases. We comprehensively discuss its role in reprogramming and modification during the regulation of glycolysis, the clinical translation prospects of the hyperpolarized lactate signal, lactyl modification in human diseases, and its application with other techniques and omics.
添加收藏
创建看单
引用
4区Q1影响因子: 3.4
跳转PDF
登录
英汉
135. A pan-cancer multi-omics analysis of lactylation genes associated with tumor microenvironment and cancer development.
期刊:Heliyon
日期:2024-03-03
DOI :10.1016/j.heliyon.2024.e27465
Background:Lactylation is a significant post-translational modification bridging the gap between cancer epigenetics and metabolic reprogramming. However, the association between lactylation and prognosis, tumor microenvironment (TME), and response to drug therapy in various cancers remains unclear. Methods:First, the expression, prognostic value, and genetic and epigenetic alterations of lactylation genes were systematically explored in a pan-cancer manner. Lactylation scores were derived for each tumor using the single-sample gene set enrichment analysis (ssGSEA) algorithm. The correlation of lactylation scores with clinical features, prognosis, and TME was assessed by integrating multiple computational methods. In addition, GSE135222 data was used to assess the efficacy of lactylation scores in predicting immunotherapy outcomes. The expression of lactylation genes in breast cancers and gliomas were verified by RNA-sequencing. Results:Lactylation genes were significantly upregulated in most cancer types. CREBBP and EP300 exhibited high mutation rates in pan-cancer analysis. The prognostic impact of the lactylation score varied by tumor type, and lactylation score was a protective factor for KIRC, ACC, READ, LGG, and UVM, and a risk factor for CHOL, DLBC, LAML, and OV. In addition, a high lactylation score was associated with cold TME. The infiltration levels of CD8 T, γδT, natural killer T cell (NKT), and NK cells were lower in tumors with higher lactylation scores. Finally, immunotherapy efficacy was worse in patients with high lactylation scores than other types. Conclusion:Lactylation genes are involved in malignancy formation. Lactylation score serves as a promising biomarker for predicting patient prognosis and immunotherapy efficacy.
添加收藏
创建看单
引用
3区Q1影响因子: 4.5
跳转PDF
登录
英汉
136. Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression.
期刊:Translational oncology
日期:2023-08-10
DOI :10.1016/j.tranon.2023.101758
Due to the enhanced glycolytic rate, cancer cells generate lactate copiously, subsequently promoting the lactylation of histones. While previous studies have explored the impact of histone lactylation in modulating gene expression, the precise role of this epigenetic modification in regulating oncogenes is largely unchartered. In this study, using breast cancer cell lines and their mutants exhibiting lactate-deficient metabolome, we have identified that an enhanced rate of aerobic glycolysis supports c-Myc expression via promoter-level histone lactylation. Interestingly, c-Myc further transcriptionally upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing of MDM4 and Bcl-x in breast cancer cells. Moreover, our results reveal that restricting the activity of critical glycolytic enzymes affects the c-Myc-SRSF10 axis to subside the proliferation of breast cancer cells. Our findings provide novel insights into the mechanisms by which aerobic glycolysis influences alternative splicing processes that collectively contribute to breast tumorigenesis. Furthermore, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.
添加收藏
创建看单
引用
2区Q1影响因子: 6.8
跳转PDF
登录
英汉
137. Lactylation prediction models based on protein sequence and structural feature fusion.
期刊:Briefings in bioinformatics
日期:2024-01-22
DOI :10.1093/bib/bbad539
Lysine lactylation (Kla) is a newly discovered posttranslational modification that is involved in important life activities, such as glycolysis-related cell function, macrophage polarization and nervous system regulation, and has received widespread attention due to the Warburg effect in tumor cells. In this work, we first design a natural language processing method to automatically extract the 3D structural features of Kla sites, avoiding potential biases caused by manually designed structural features. Then, we establish two Kla prediction frameworks, Attention-based feature fusion Kla model (ABFF-Kla) and EBFF-Kla, to integrate the sequence features and the structure features based on the attention layer and embedding layer, respectively. The results indicate that ABFF-Kla and Embedding-based feature fusion Kla model (EBFF-Kla), which fuse features from protein sequences and spatial structures, have better predictive performance than that of models that use only sequence features. Our work provides an approach for the automatic extraction of protein structural features, as well as a flexible framework for Kla prediction. The source code and the training data of the ABFF-Kla and the EBFF-Kla are publicly deposited at: https://github.com/ispotato/Lactylation_model.
添加收藏
创建看单
引用
4区Q3影响因子: 1.9
跳转PDF
登录
英汉
138. Histone Lactylation Participates in Psoriasis Progression by Regulating the Adiponectin Expression.
期刊:Clinical, cosmetic and investigational dermatology
日期:2024-01-26
DOI :10.2147/CCID.S450254
Background:Psoriasis is a chronic inflammatory skin disease characterized by erythema, papules, and plaques. Adiponectin (ADIPOQ) is an important protein hormone secreted by adipose tissue. Here, we aimed to explore the expression of ADIPOQ in psoriasis patients and the moderation effect of histone lactylation on ADIPOQ. Methods:The GSE78097 data set was downloaded from GEO database to analyze the differentially expressed genes (DEGs) in psoriasis. A total of 36 psoriasis patients were recruited to obtain the skin samples. The ADIPOQ protein levels, global lactylation and histone lactylation (H3K18lac) levels were detected by Western blot assay. Chromatin immunoprecipitation (CHIP) assay was performed to detect the combination between H3K18lac and promoter regions of the ADIPOQ. The receiver operating curve (ROC) analysis was used to evaluate the diagnostic value of ADIPOQ in psoriasis. Results:ADIPOQ was decreased in the skin tissues of psoriasis patients. In addition, the global lactylation and H3K18lac levels were significantly decreased in the skin tissues of psoriasis patients. In HaCaT cells, promoting the global lactylation and H3K18lac levels increased the ADIPOQ protein levels, while si-LDHA transfection decreased the ADIPOQ protein levels. The CHIP results indicated that lactylation promoted the binding of promoter regions of the ADIPOQ and H3K18lac. Finally, the ROC analysis showed that ADIPOQ exhibited diagnostic value in psoriasis. Conclusion:This study demonstrated ADIPOQ was decreased in the skin tissues of psoriasis patients, and ADIPOQ has diagnostic value for psoriasis. Furthermore, down-regulation of H3K18lac levels inhibited the transcription of ADIPOQ, which was the key factor of decrease of ADIPOQ levels in psoriasis patients.
添加收藏
创建看单
引用
3区Q2影响因子: 3.2
跳转PDF
登录
英汉
139. Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
期刊:Molecular and cellular biology
日期:2023-10-11
DOI :10.1080/10985549.2023.2253131
During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.
添加收藏
创建看单
引用
4区Q4影响因子: 1.6
跳转PDF
登录
英汉
140. Pathophysiological Implications of Protein Lactylation in Pancreatic Epithelial Tumors.
期刊:Acta histochemica et cytochemica
日期:2024-04-04
DOI :10.1267/ahc.24-00010
Protein lactylation is a post-translational modification associated with glycolysis. Although recent evidence indicates that protein lactylation is involved in epigenetic gene regulation, its pathophysiological significance remains unclear, particularly in neoplasms. Herein, we investigated the potential involvement of protein lactylation in the molecular mechanisms underlying benign and malignant pancreatic epithelial tumors, as well as its role in the response of pancreatic cancer (PC) cells to gemcitabine. Increased lactylation was observed in the nuclei of intraductal papillary mucinous adenoma, non-invasive intraductal papillary mucinous carcinoma, and invasive carcinoma, in parallel to the upregulation of hypoxia-inducible factor-1α. This observation indicated that a hypoxia-associated increase in nuclear protein lactylation could be a biochemical hallmark in pancreatic epithelial tumors. The standard PC chemotherapy drug gemcitabine suppressed histone lactylation , suggesting that histone lactylation might be relevant to its mechanism of action. Taken together, our findings suggest that protein lactylation may be involved in the development of pancreatic epithelial tumors and could represent a potential therapeutic target for PC.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
141. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
期刊:Cell reports
日期:2025-03-18
DOI :10.1016/j.celrep.2025.115441
Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.
添加收藏
创建看单
引用
1区Q1影响因子: 13
跳转PDF
登录
英汉
142. Lactylation of tau in human Alzheimer's disease brains.
期刊:Alzheimer's & dementia : the journal of the Alzheimer's Association
日期:2024-12-30
DOI :10.1002/alz.14481
INTRODUCTION:Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation. METHODS:We analyzed lactylation of tau in control and AD brain tissue and conducted cell-based assays. In addition, we used in vitro assays to determine whether p300 catalyzed tau lactylation. RESULTS:Quantitative proteomics detected that tau lactylation was elevated in AD brains, with K residue at position 331 (K331) being a prominent site. Lactate induced tau lactylation, which increased tau phosphorylation and cleavage and reduced ubiquitination. Inhibition of lactate production lowered tau lactylation; p300 catalyzed tau lactylation. DISCUSSION:Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target. HIGHLIGHTS:Elevated tau lactylation, particularly at K331, is evident in in human AD brain samples. Lactate induces tau lactylation, enhancing phosphorylation and cleavage while inhibiting ubiquitination. The acetyl-transferase p300 catalyzes tau lactylation, with K331 being the most prominent site.
添加收藏
创建看单
引用
1区Q1影响因子: 13.3
跳转PDF
登录
英汉
143. Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.
期刊:The Journal of clinical investigation
日期:2025-01-30
DOI :10.1172/JCI187024
Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 13
英汉
144. Current and future perspectives of lysine lactylation in cancer.
期刊:Trends in cell biology
日期:2025-01-20
DOI :10.1016/j.tcb.2024.12.015
Lactate, a glycolytic intermediate, has a crucial role in cancer metabolism and microenvironment remodeling. Recently, researchers found that lactate mediates lysine lactylation, a novel protein post-translational modification (PTM). Here, we summarize the mechanism and role of lysine lactylation in cancer, and discuss the potential of targeting lysine lactylation in cancer therapy.
添加收藏
创建看单
引用
1区Q1影响因子: 29.7
英汉
145. Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.
期刊:Cancer discovery
日期:2025-02-28
DOI :10.1158/2159-8290.CD-24-1056
Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.
添加收藏
创建看单
引用
1区Q1影响因子: 14.5
英汉
146. The role of protein lactylation: A kaleidoscopic post-translational modification in cancer.
期刊:Molecular cell
日期:2025-03-11
DOI :10.1016/j.molcel.2025.02.011
The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment.
添加收藏
创建看单
引用
1区Q1影响因子: 25.5
打开PDF
登录
英汉
147. Lactate: A key regulator of the immune response.
期刊:Immunity
日期:2025-03-11
DOI :10.1016/j.immuni.2025.02.008
Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
打开PDF
登录
英汉
148. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
期刊:Cell metabolism
日期:2024-12-05
DOI :10.1016/j.cmet.2024.11.005
Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
149. H3K9 lactylation in malignant cells facilitates CD8 T cell dysfunction and poor immunotherapy response.
期刊:Cell reports
日期:2024-08-30
DOI :10.1016/j.celrep.2024.114686
Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8 T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8 T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8 T cell exhaustion, and cholesterol-modified siIL11 restores CD8 T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.
添加收藏
创建看单
引用
1区Q1影响因子: 12.9
跳转PDF
登录
英汉
150. Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis.
期刊:Nature chemical biology
日期:2024-07-19
DOI :10.1038/s41589-024-01680-8
Lysine L-lactylation (K) is a novel protein posttranslational modification (PTM) driven by L-lactate. This PTM has three isomers: K, N-ε-(carboxyethyl)-lysine (K) and D-lactyl-lysine (K), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that K is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not K or K, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in L-lactylation, correlates positively with K levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights K as the primary responder to glycolysis and the Warburg effect.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
151. Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation.
期刊:Cell metabolism
日期:2024-11-21
DOI :10.1016/j.cmet.2024.10.019
The effect of the serine/glycine-free diet (-SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the -SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the -SG diet, indicating the potential of combining the -SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the -SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the -SG diet for treating solid tumors.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
152. Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.
期刊:Cell reports
日期:2024-01-19
DOI :10.1016/j.celrep.2024.113688
Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
BACKGROUND:Lactylation, a post-translational modification, is increasingly recognized for its role in cancer progression. This study investigates its prevalence and impact in oral squamous cell carcinoma (OSCC). RESULTS:Immunohistochemical staining of 81 OSCC cases shows lactylation levels correlate with malignancy grading. Proteomic analyses of six OSCC tissue pairs reveal 2765 lactylation sites on 1033 proteins, highlighting its extensive presence. These modifications influence metabolic processes, molecular synthesis, and transport. CAL27 cells are subjected to cleavage under targets and tagmentation assay for accessible-chromatin with high-throughput sequencing, and transcriptomic sequencing pre- and post-lactate treatment, with 217 genes upregulated due to lactylation. Chromatin immunoprecipitation-quantitative PCR and real-time fluorescence quantitative PCR confirm the regulatory role of lactylation at the K146 site of dexh-box helicase 9 (DHX9), a key factor in OSCC progression. CCK8, colony formation, scratch healing, and Transwell assays demonstrate that lactylation mitigates the inhibitory effect of DHX9 on OSCC, thereby promoting its occurrence and development. CONCLUSIONS:Lactylation actively modulates gene expression in OSCC, with significant effects on chromatin structure and cellular processes. This study provides a foundation for developing targeted therapies against OSCC, leveraging the role of lactylation in disease pathogenesis.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
154. Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation.
期刊:Cell reports
日期:2023-01-31
DOI :10.1016/j.celrep.2023.112033
Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation.
添加收藏
创建看单
引用
2区Q1影响因子: 16.6
跳转PDF
登录
英汉
155. Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A.
期刊:Nucleic acids research
日期:2024-03-21
DOI :10.1093/nar/gkad1193
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
156. Histone lactylation drives CD8 T cell metabolism and function.
期刊:Nature immunology
日期:2024-10-07
DOI :10.1038/s41590-024-01985-9
The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8 T cells, which act as transcription initiators of key genes regulating CD8 T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8 T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8 T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8 T cells.
添加收藏
创建看单
引用
1区Q1影响因子: 26.8
打开PDF
登录
英汉
157. Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD.
期刊:Journal of hepatology
日期:2024-04-27
DOI :10.1016/j.jhep.2024.04.010
BACKGROUND & AIMS:Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. METHODS:Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. RESULTS:Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. CONCLUSION:NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. IMPACT AND IMPLICATIONS:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
跳转PDF
登录
英汉
158. Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
期刊:Cell reports
日期:2024-08-09
DOI :10.1016/j.celrep.2024.114607
Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
添加收藏
创建看单
引用
1区Q1影响因子: 36.1
英汉
159. Uncovering ubiquitous protein lactylation.
期刊:Nature methods
日期:2022-07-01
DOI :10.1038/s41592-022-01536-w
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
160. The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.
期刊:Cell metabolism
日期:2023-08-04
DOI :10.1016/j.cmet.2023.07.005
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
161. ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion.
期刊:Cell metabolism
日期:2024-11-18
DOI :10.1016/j.cmet.2024.10.015
Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
162. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells.
期刊:Cell reports
日期:2022-06-21
DOI :10.1016/j.celrep.2022.110986
Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is a crucial metabolite in cancer and is related to tumor prognosis, metastasis, and overall survival. In this study, we focus on the effects of lactate on Treg cells. In vitro, lactate improves Treg cell stability and function, whereas lactate degradation reduces Treg cell induction, increases antitumor immunity, and decreases tumor growth in mice. Mechanistically, lactate modulates Treg cell generation through lactylation of Lys72 in MOESIN, which improves MOESIN interaction with transforming growth factor β (TGF-β) receptor I and downstream SMAD3 signaling. Cotreatment with anti-PD-1 and a lactate dehydrogenase inhibitor has a stronger antitumor effect than anti-PD-1 alone. Individuals with hepatocellular carcinoma who responded to anti-PD-1 treatment have lower levels of MOESIN lactylation in Treg cells than nonresponding individuals. Thus, we identify lactate as an essential small molecule that reinforces Treg cells in the tumor microenvironment through lactylation.
添加收藏
创建看单
引用
1区Q1影响因子: 13.3
跳转PDF
登录
英汉
163. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
期刊:The Journal of clinical investigation
日期:2024-11-15
DOI :10.1172/JCI176851
Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
添加收藏
创建看单
引用
1区Q1影响因子: 13.6
英汉
164. Histone lactylation: epigenetic mark of glycolytic switch.
作者:Dai Xiaofeng , Lv Xinyu , Thompson Erik W , Ostrikov Kostya Ken
期刊:Trends in genetics : TIG
日期:2021-10-07
DOI :10.1016/j.tig.2021.09.009
Histone lactylation and acetylation compete for epigenetic modification of lysines and mark the levels of lactates and acetyl-CoA. Whether pyruvate is committed to lactate or acetyl-CoA generation as the outlet of glycolysis determines cell fate towards malignancy or not. Taking control over the glycolytic switch as marked by lactylation suggests novel therapeutic opportunities against cancers.
Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3 GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3 GBM.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
英汉
166. Lactylation: Linking the Warburg effect to DNA damage repair.
期刊:Cell metabolism
日期:2024-08-06
DOI :10.1016/j.cmet.2024.06.015
In this issue of Cell Metabolism, Li et al. report that the highly expressed aldehyde dehydrogenase 1 family member A3 interacts with pyruvate kinase M2 (PKM2) in glioblastoma cells. Consequently, PKM2 tetramerization and activation promote lactate production, leading to the lactylation and nuclear translocation of XRCC1 for DNA damage repair and therapeutic resistance.
添加收藏
创建看单
引用
1区Q1影响因子: 11.7
打开PDF
登录
英汉
167. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.
期刊:Science advances
日期:2022-01-19
DOI :10.1126/sciadv.abi6696
Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε--L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements.
添加收藏
创建看单
引用
1区Q1影响因子: 11.7
跳转PDF
登录
英汉
168. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation.
期刊:Science advances
日期:2023-06-02
DOI :10.1126/sciadv.adg4993
Autophagy and glycolysis are highly conserved biological processes involved in both physiological and pathological cellular programs, but the interplay between these processes is poorly understood. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is activated upon UNC-51-like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients are scarce and promotes lactate production. Lactate connects autophagy and glycolysis through Vps34 lactylation (at lysine-356 and lysine-781), which is mediated by the acyltransferase KAT5/TIP60. Vps34 lactylation enhances the association of Vps34 with Beclin1, Atg14L, and UVRAG, and then increases Vps34 lipid kinase activity. Vps34 lactylation promotes autophagic flux and endolysosomal trafficking. Vps34 lactylation in skeletal muscle during intense exercise maintains muscle cell homeostasis and correlates with cancer progress by inducing cell autophagy. Together, our findings describe autophagy regulation mechanism and then integrate cell autophagy and glycolysis.
添加收藏
创建看单
引用
1区Q1影响因子: 25.5
跳转PDF
登录
英汉
169. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
期刊:Immunity
日期:2024-05-03
DOI :10.1016/j.immuni.2024.04.006
Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.
添加收藏
创建看单
引用
1区Q1影响因子: 45.5
打开PDF
登录
英汉
170. Metabolic regulation of homologous recombination repair by MRE11 lactylation.
期刊:Cell
日期:2023-12-20
DOI :10.1016/j.cell.2023.11.022
Lactylation is a lactate-induced post-translational modification best known for its roles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologous recombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase in response to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylation promotes its binding to DNA, facilitating DNA end resection and HR. Inhibition of CBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivity of tumor cells in patient-derived xenograft and organoid models. A cell-penetrating peptide that specifically blocks MRE11 lactylation inhibited HR and sensitized cancer cells to cisplatin and PARPi. These findings unveil lactylation as a key regulator of HR, providing fresh insights into the ways in which cellular metabolism is linked to DSB repair. They also imply that the Warburg effect can confer chemoresistance through enhancing HR and suggest a potential therapeutic strategy of targeting MRE11 lactylation to mitigate the effects.
添加收藏
创建看单
引用
1区Q1影响因子: 45.5
打开PDF
登录
英汉
171. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.
期刊:Cell
日期:2024-04-22
DOI :10.1016/j.cell.2024.04.002
Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
打开PDF
登录
英汉
172. AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.
期刊:Nature
日期:2024-09-25
DOI :10.1038/s41586-024-07992-y
L-lactate modifies proteins through lactylation, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensors required for L-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of L-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular L-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.
添加收藏
创建看单
引用
1区Q1影响因子: 13.3
跳转PDF
登录
英汉
173. The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.
期刊:The Journal of clinical investigation
日期:2024-03-21
DOI :10.1172/JCI174587
Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.
添加收藏
创建看单
引用
1区Q1影响因子: 14.5
打开PDF
登录
英汉
174. Lactylation-driven METTL3-mediated RNA mA modification promotes immunosuppression of tumor-infiltrating myeloid cells.
期刊:Molecular cell
日期:2022-03-22
DOI :10.1016/j.molcel.2022.02.033
Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N-methyladenosine (mA) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated mA modification on Jak1 mRNA in TIMs, the mA-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA mA modification for promoting the immunosuppressive capacity of TIMs.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
打开PDF
登录
英汉
175. Lactylation in cancer: Current understanding and challenges.
期刊:Cancer cell
日期:2024-10-10
DOI :10.1016/j.ccell.2024.09.006
Lactylation, a recently identified post-translational modification, has initially been linked to gene transcription regulation through epigenetic mechanisms. However, its role in tumorigenesis-whether as a major driver or a minor regulator-remains uncertain. Here, we summarize the current understanding of lactylation and discuss the inherent challenges in definitively attributing specific biological roles to this modification. We emphasize the necessity for precise methodologies to manipulate lactylation levels within pathophysiologically relevant conditions. Further investigation is required to determine whether lactylation plays a critical role in tumor biology or merely reflects secondary metabolic alterations.
添加收藏
创建看单
引用
1区Q1影响因子: 28.1
打开PDF
登录
英汉
176. Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.
期刊:Cell research
日期:2024-01-02
DOI :10.1038/s41422-023-00864-6
Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
添加收藏
创建看单
引用
1区Q1影响因子: 50.5
打开PDF
登录
英汉
177. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.
期刊:Nature
日期:2024-07-03
DOI :10.1038/s41586-024-07620-9
The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.
添加收藏
创建看单
引用
1区Q1影响因子: 45.9
英汉
178. Lactylation and HCC progression.
期刊:Nature reviews. Gastroenterology & hepatology
日期:2023-03-01
DOI :10.1038/s41575-023-00746-7
添加收藏
创建看单
引用
2区Q1影响因子: 4.8
英汉
179. Prognostic model of osteosarcoma based on telomere-related genes and analysis of immune characteristics.
期刊:International immunopharmacology
日期:2025-02-20
DOI :10.1016/j.intimp.2025.114198
OBJECTIVE:Osteosarcoma is a malignant tumor with significant challenges in treatment and prognosis. Telomeres play a crucial role in genetic stability and tumor development, and telomere-related genes (TRGs) have shown considerable prognostic potential in various cancers. However, the prognostic significance of TRGs in osteosarcoma and their involvement in the tumor immune microenvironment (TIME) remain poorly understood. METHOD:This study initially identified 2086 TRGs from the TelNet database as candidate genes. Using RNA sequencing and clinical data from osteosarcoma patients available in the TARGET and GEO public databases, we developed a TRG-based prognostic scoring model through univariate, LASSO regression, and multivariate Cox regression analyses, with its predictive performance subsequently validated. Unsupervised clustering was performed on TRGs associated with prognosis. To investigate the TIME, we utilized several algorithms including ESTIMATE, CIBERSORT, xCELL, and ssGSEA to analyze the immune landscape associated with TRG patterns. Additionally, functional enrichment analysis of different subtypes was conducted using KEGG, GO, and GSVA approaches. We also performed single-cell localization and drug sensitivity analysis on the prognostic model genes. Finally, the predictive results were preliminarily validated through a series of in vitro experiments. RESULT:Differential expression analysis revealed 841 TRGs with significant changes in osteosarcoma, where P-value < 0.05 and |logFC| ≥ 1. Based on the prognostic relevance of these TRGs, we successfully identified two subtypes with distinct clinical and immune characteristics. Immune infiltration levels between Cluster 1 and Cluster 2 were significantly different, as assessed by multiple algorithms. Furthermore, we constructed a prognostic scoring model based on TRGs, which demonstrated excellent predictive performance, with AUC values for 1-year, 3-year, and 5-year ROC curves being 92.43 %, 87.08 %, and 84.34 % in the training cohort, respectively, and 74.49 %, 87.77 %, and 94.52 % in the validation cohort, indicating good stability of the model. Notably, functional enrichment analysis highlighted a strong association between immune dysfunction and poor prognosis, while drug sensitivity analysis offered personalized chemotherapy recommendations for osteosarcoma patients with different subtypes. We observed that Fludarabine had a higher IC50 value in the high-risk group compared to the low-risk group, and it showed a strong correlation with the prognostic model genes, with all P-values less than 0.05. CONCLUSION:This study successfully constructed a prognostic risk prediction model for osteosarcoma by systematically analyzing the expression patterns of TRGs. Fludarabine may represent a promising therapeutic option for patients with osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
180. Localized Nanoparticle-Mediated Delivery of miR-29b Normalizes the Dysregulation of Bone Homeostasis Caused by Osteosarcoma whilst Simultaneously Inhibiting Tumor Growth.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-04-25
DOI :10.1002/adma.202207877
Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localized delivery of miR-29b-which is shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and cervical tumor growth-can suppress osteosarcoma tumors whilst simultaneously normalizing the dysregulation of bone homeostasis caused by osteosarcoma. Thus, the therapeutic potential of microRNA (miR)-29b is studied to promote bone remodeling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. A formulation of miR-29b:nanoparticles are developed that are delivered via a hyaluronic-based hydrogel to enable local and sustained release of the therapy and to study the potential of attenuating tumor growth whilst normalizing bone homeostasis. It is found that when miR-29b is delivered along with systemic chemotherapy, compared to chemotherapy alone, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in osteolysis thereby normalizing the dysregulation of bone lysis activity caused by the tumor.
添加收藏
创建看单
引用
1区Q1影响因子: 45.5
英汉
181. Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution.
期刊:Cell
日期:2025-01-14
DOI :10.1016/j.cell.2024.12.005
Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 22.5
跳转PDF
登录
英汉
182. Activity of Cabazitaxel in Metastatic or Inoperable Locally Advanced Dedifferentiated Liposarcoma: A Phase 2 Study of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG).
期刊:JAMA oncology
日期:2022-10-01
DOI :10.1001/jamaoncol.2022.3218
Importance:Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required. Objective:To assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting. Design, Setting, and Participants:This international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. Interventions:After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. Main Outcomes and Measures:The primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. Results:Forty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%). Conclusions and Relevance:This nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.
添加收藏
创建看单
引用
2区Q1影响因子: 16.6
英汉
183. Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers.
期刊:Nucleic acids research
日期:2025-02-08
DOI :10.1093/nar/gkaf061
The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent mechanism for immortalization in cancer cells and is commonly activated in low-grade and high-grade glioma, as well as osteosarcoma. The ALT pathway can be activated under various conditions and has often been shown to include mutational loss of ATRX. However, this is insufficient in isolation and so other cellular event must also be implicated. It has been shown that excessive accumulation of DNA:RNA hybrid structures (R-loops) and/or formation of DNA-protein crosslinks (DPCs) can be other important driving factors. The underlying cellular events leading to R-loop and DPC formation in ALT cancer cells to date remain unclear. Here, we demonstrate that excessive cellular reactive oxygen species (ROS) is an important causative factor in the evolution of ALT-telomere maintenance in ATRX-deficient glioma. We identified three sources of elevated ROS in ALT-positive gliomas: co-mutation of SETD2, downregulation of DRG2, and hypoxic tumour microenvironment. We demonstrate that elevated ROS leads to accumulation of R-loops and, crucially, resolution of R-loops by the enzyme RNase H1 prevents ALT pathway activity in cells exposed to elevated ROS. Further, we found a possible causal link between the formation of R-loops and the accumulation of DPCs, in particular, formation of TOP1 complexes covalently linked to DNA (Top1cc). We also demonstrate that elevation of ROS can trigger over-activity of the ALT pathway in osteosarcoma and glioma cell lines, resulting in excessive DNA damage and cell death. This work presents important mechanistic insights into the endogenous origin of excessive R-loops and DPCs in ALT-positive cancers, as well as highlighting potential novel therapeutic approaches in these difficult-to-treat cancer types.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
跳转PDF
登录
英汉
184. Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma.
期刊:Cell reports
日期:2021-01-26
DOI :10.1016/j.celrep.2020.108678
Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
185. Engineering Single-Atomic Iron-Catalyst-Integrated 3D-Printed Bioscaffolds for Osteosarcoma Destruction with Antibacterial and Bone Defect Regeneration Bioactivity.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2021-06-19
DOI :10.1002/adma.202100150
Effective antitumor therapeutics with distinctive bactericidal and osteogenic properties are in high demand for comprehensive osteosarcoma treatment. Here, a "scaffold engineering" strategy that integrates highly active single-atomic iron catalysts (FeSAC) into a 3D printed bioactive glass (BG) scaffold is reported. Based on the atomically dispersed iron species within the catalysts, the engineered FeSAC displays prominent Fenton catalytic activity to generate toxic hydroxyl radicals (•OH) in response to the microenvironment specific to osteosarcoma. In addition, the constructed FeSAC-BG scaffold can serve as a sophisticated biomaterial platform for efficient osteosarcoma ablation, with concomitant bacterial sterilization via localized hyperthermia-reinforced nanocatalytic therapeutics. The destruction of the osteosarcoma, as well as the bacterial foci, can be achieved, further preventing susceptible chronic osteomyelitis during osteogenesis. In particular, the engineered FeSAC-BG scaffold is identified with advances in accelerated osteoconduction and osteoinduction, ultimately contributing to the sophisticated therapeutics and management of osteosarcoma. This work broadens the biomedical potential of single-atom catalysts and offers a comprehensive clinically feasible strategy for overall osteosarcoma therapeutics, bacterial inhibition, and tissue regeneration.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
186. Bone Destruction-Chemotactic Osteoprogenitor Cells Deliver Liposome Nanomedicines for the Treatment of Osteosarcoma and Osteoporosis.
期刊:ACS nano
日期:2024-10-18
DOI :10.1021/acsnano.4c10053
Therapeutic efficacy of skeletal diseases is usually limited by unfavorable drug delivery due to incapable bone targeting and low bone affinity of conventional drug carriers, as well as relatively reduced vascularization and dense structure of bone tissues. Due to CXC chemokine receptor 4 (CXCR4)/CXC chemokine ligand 12 (CXCL12) signal axis-guided recruitment, osteoprogenitor cells (OPCs) can actively migrate to bone disease nidus. Here, drugs-loaded nanoliposomes are prepared and decorated onto OPCs by biotin-streptavidin linkage for precise bone disease targeting and effective drug delivery. In mouse models of tibia defect and orthotopic osteosarcoma, superior targeting property of OPCs-based drug delivery systems toward diseased bone niduses is verified. By encapsulating antitumor and antiosteoporosis drugs into nanoliposomes, OPCs-based drug delivery systems effectively inhibit disease development and restore bone destruction in mouse models of orthotopic osteosarcoma and ovariectomized osteoporosis. This study reveals a cell-based drug delivery system for precise bone disease targeting and highly effective drug delivery, which will find great potential as a universal drug delivery platform for targeting treatment of various bone diseases.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
187. Pathological Fracture and Prognosis of High-Grade Osteosarcoma of the Extremities: An Analysis of 2,847 Consecutive Cooperative Osteosarcoma Study Group (COSS) Patients.
作者:Kelley Lisa Marie , Schlegel Miriam , Hecker-Nolting Stefanie , Kevric Matthias , Haller Bernhard , Rössig Claudia , Reichardt Peter , Kager Leo , Kühne Thomas , Gosheger Georg , Windhager Reinhard , Specht Katja , Rechl Hans , Tunn Per-Ulf , Baumhoer Daniel , Wirth Thomas , Werner Mathias , von Kalle Thekla , Nathrath Michaela , Burdach Stefan , Bielack Stefan , von Lüttichau Irene
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2020-01-13
DOI :10.1200/JCO.19.00827
PURPOSE:The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities. METHODS:We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients. RESULTS:A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively ( = .007), and 5-year event-free survival (EFS) was 51% versus 58% ( = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% ( < .001), and 5-year EFS was 36% versus 56% ( < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS ( = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS ( = .263; HR, 1.312). CONCLUSION:In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
188. Chemotherapy-Sensitized Vaccination for Malignant Osteosarcoma Enabled by Bioinspired Calcium Phosphonate Nanoagents.
期刊:ACS nano
日期:2023-03-24
DOI :10.1021/acsnano.2c09685
How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously eliciting antitumor immunity. However, targeted chemoimmunotherapy lacks a reliable delivery system. To address this issue, we herein developed a bioinspired calcium phosphonate nanoagent that was synthesized by chemical reactions between Ca and phosphonate residue from zoledronic acid using bovine serum albumin as a scaffold. In addition, methotrexate combination with a phosphorothioate CpG immunomodulator was also loaded for pH-responsive delivery to enable synergistic chemoimmunotherapy of osteosarcoma. The calcium phosphonate nanoagents were found to effectively accumulate in osteosarcoma for nearly 1 week, which is favorable for exerting the vaccination effects by maturing dendritic cells and priming CD8 T cells to suppress the osteosarcoma progression and pulmonary metastasis through controlled release of the three loaded agents in the acidic tumor microenvironment. The current study may thus offer a reliable delivery platform for achieving targeted chemotherapy-induced antitumor immunity.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
189. An "Outer Piezoelectric and Inner Epigenetic" Logic-Gated PANoptosis for Osteosarcoma Sono-Immunotherapy and Bone Regeneration.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2024-12-27
DOI :10.1002/adma.202415814
The precise manipulation of PANoptosis, a newly defined cell death pathway encompassing pyroptosis, apoptosis, and necroptosis, is highly desired to achieve safer cancer immunotherapy with tumor-specific inflammatory responses and minimal side effects. Nonetheless, this objective remains a formidable challenge. Herein, an "AND" logic-gated strategy for accurately localized PANoptosis activation, utilizing composite 3D-printed bioactive glasses scaffolds integrated with epigenetic regulator-loaded porous piezoelectric SrTiO nanoparticles is proposed. The "logic-gated" strategy is co-programmed by an "outer" input signal of exogenous ultrasound irradiation to produce reactive oxygen species and an "inner" input signal of acid tumor microenvironment to ensure the epigenetic demethylation regulation, guaranteeing the tumor-specific PANoptosis. Specifically, immunogenic PANoptosis triggers dendritic cell maturation and cytotoxic T cell activation, amplifying antitumor immune responses and significantly suppressing osteosarcoma growth, with a suppression rate of ≈73.47 ± 5.2%. In addition, the well-known bioactivities of Sr-doped scaffolds expedite osteogenic differentiation and reinforce bone regeneration. Therefore, this work provides a paradigm of logic-gated sono-piezoelectric biomaterial platform with concurrently exogenous/endogenous activated PANoptosis for controlled sono-immunotherapy of osteosarcoma, and related bone defects repair.
添加收藏
创建看单
引用
1区Q1影响因子: 11.7
跳转PDF
登录
英汉
190. Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer.
期刊:Science advances
日期:2021-02-10
DOI :10.1126/sciadv.abd7459
The lipogenic enzyme stearoyl CoA desaturase (SCD) plays a key role in tumor lipid metabolism and membrane architecture. SCD is often up-regulated and a therapeutic target in cancer. Here, we report the unexpected finding that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and unintentional monoallelic co-deletion with phosphatase and tensin homolog (PTEN) in a subset of patients. Cell lines from this subset expressed undetectable SCD, yet retained residual SCD enzymatic activity. Unexpectedly, these lines evolved to survive independent of SCD through unknown mechanisms. Cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Last, we identify that SCD-dependent lines acquire resistance through a previously unknown FBJ murine osteosarcoma viral oncogene homolog B (FOSB)-mediated mechanism. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor-bearing mice treated with SCD inhibitor.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
191. One-Dimensional Ferroelectric Nanoarrays with Wireless Switchable Static and Dynamic Electrical Stimulation for Selective Regulating Osteogenesis and Antiosteosarcoma.
期刊:ACS nano
日期:2022-11-22
DOI :10.1021/acsnano.2c07900
Preventing local tumor recurrence and simultaneously improving bone-tissue regeneration are in great demand for osteosarcoma therapy. However, the current therapeutic implants fail to selectively suppress tumor growth and enhance osteogenesis, and antitumor therapy may compromise osseointegration of the bone implant. Here, based on the different responses of bone tumor cells and osteoblasts to different electric stimulations, we constructed ferroelectric BaTiO nanorod arrays (NBTO) on the surface of titanium implants with switchable dynamic and static electrical stimulation for selective bone-tumor therapy and bone tissue regeneration. Polarized NBTO (PNBTO) generated a sustained dynamic electrical stimulus in response to wireless ultrasonic irradiation ("switch-on"), which disrupted the orientation of the spindle filaments of the tumor cell, blocked the G2/M phase of mitosis, and ultimately led to tumor cell death, whereas it had almost no cytotoxic effect on normal bone cells. Under the switch-off state, PNBTO with a high surface potential provided static electrical stimulation, accelerating osteogenic differentiation of mesenchymal stem cells and enhancing the quality of bone regeneration both and . This study broadens the biomedical potential of electrical stimulation therapy and provides a comprehensive and clinically feasible strategy for the overall treatment and tissue regeneration in osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
打开PDF
登录
英汉
192. FOS licenses early events in stem cell activation driving skeletal muscle regeneration.
期刊:Cell reports
日期:2021-01-26
DOI :10.1016/j.celrep.2020.108656
Muscle satellite cells (SCs) are a quiescent (non-proliferative) stem cell population in uninjured skeletal muscle. Although SCs have been investigated for nearly 60 years, the molecular drivers that transform quiescent SCs into the rapidly dividing (activated) stem/progenitor cells that mediate muscle repair after injury remain largely unknown. Here we identify a prominent FBJ osteosarcoma oncogene (Fos) mRNA and protein signature in recently activated SCs that is rapidly, heterogeneously, and transiently induced by muscle damage. We further reveal a requirement for FOS to efficiently initiate key stem cell functions, including cell cycle entry, proliferative expansion, and muscle regeneration, via induction of "pro-regenerative" target genes that stimulate cell migration, division, and differentiation. Disruption of one of these Fos/AP-1 targets, NAD(+)-consuming mono-ADP-ribosyl-transferase 1 (Art1), in SCs delays cell cycle entry and impedes progenitor cell expansion and muscle regeneration. This work uncovers an early-activated FOS/ART1/mono-ADP-ribosylation (MARylation) pathway that is essential for stem cell-regenerative responses.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
193. Additively Manufactured Biodegradable Zn-Based Porous Scaffolds to Suppress Osteosarcoma and Promote Osteogenesis.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2024-11-20
DOI :10.1002/adma.202410589
Postoperative therapies for osteosarcoma present substantial challenges due to tumor recurrence and extensive bone defects. To tackle these challenges, laser powder bed fusion is utilized to fabricate biodegradable Zn-Li porous scaffolds that supress tumors and promote osteogenesis. After the structure design and composition selection, the Zn-0.8Li porous scaffold with Gyroid unit optimally balances the co-release of Zn and Li during degradation, resulting in favorable antitumor and osteogenic effects. In vitro, the Zn-0.8Li scaffold significantly inhibits osteosarcoma progression by suppressing tumor cell proliferation, promoting apoptosis, alleviating migration, and simultaneously promotes osteogenic differentiation through the enhanced expression of osteogenic markers. In vivo, the Zn-0.8Li scaffold inhibits the malignant osteosarcoma behavior and facilitates bone regeneration in areas with bone defects. Transcriptomic analysis further reveals that the simultaneous release of Zn and Li from the biodegradable Zn-0.8Li scaffold contributes to anti-osteosarcoma activity by downregulating PI3K/Akt signaling pathways. Taken together, the Zn-0.8Li porous scaffold fabricated using laser powder bed fusion with enhanced antitumor and osteogenic properties is a promising alternative for the postoperative management of osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
194. Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2023-05-26
DOI :10.1200/JCO.22.02045
PURPOSE:Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS:Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS:The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION:To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
195. A Unified Therapeutic-Prophylactic Tissue-Engineering Scaffold Demonstrated to Prevent Tumor Recurrence and Overcoming Infection toward Bone Remodeling.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-05-02
DOI :10.1002/adma.202300313
Osteosarcoma occurs in children and adolescents frequently and leads to a high fatality rate. Although surgical resection is the most common methods in clinic, patients always suffer from tumor metastasis and recurrence and it is difficult for them to self-repair large bone defects. Furthermore, the postoperative infection from bacteria triggers an inflammatory response and hinders the bone-repair process. This work demonstrates a gadolinium (Gd)-complex and molybdenum sulfide (MoS ) co-doped N-acryloyl glycinamide (NAGA)/gelatin methacrylate (Gel-MA) multifunctional hydrogel (GMNG). The combination between NAGA and Gel-MA endows the GMNG with attractive mechanical properties and controllable degradation ability. The MoS improves the hydrogel system, which has excellent photothermal ability to kill tumor cells and inhibit bacterial infection both in vitro and in vivo. Based on the Gd-complex, the magnetic resonance imaging (MRI) effect can be used to monitor the position and degradation situation of the hydrogel. Notably, accompanied by the degradation of GMNG hydrogel, the gradually released Gd from the hydrogel exhibits osteogenic property and could promote new bone formation efficiently in vivo. Therefore, this strategy supplies a method to prepare multifunctional bone-defect-repair materials and is expected to represent a significant guidance and reference to the development of biomaterials for bone tissue engineering.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
打开PDF
登录
英汉
196. Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.
期刊:Cell reports
日期:2021-11-23
DOI :10.1016/j.celrep.2021.110047
We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
197. Acidity-Triggered Transformable Polypeptide Self-Assembly to Initiate Tumor-Specific Biomineralization.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-02-26
DOI :10.1002/adma.202203291
Biomineralization is a normal physiological process that includes nucleation, crystal growth, phase transformation, and orientation evolution. Notably, artificially induced biomineralization in the tumor tissue has emerged as an unconventional yet promising modality for malignancy therapy. However, the modest ion-chelating capabilities of carboxyl-containing biomineralization initiators lead to a deficient blockade, thus compromising antitumor efficacy. Herein, a biomineralization-inducing nanoparticle (BINP) is developed for blockade therapy of osteosarcoma. BINP is composed of dodecylamine-poly((γ-dodecyl-l-glutamate)-co-(l-histidine))-block-poly(l-glutamate-graft-alendronate) and combines a cytomembrane-insertion moiety, a tumor-microenvironment (TME)-responsive component, and an ion-chelating motif. After intravenous injection into osteosarcoma-bearing mice, BINP responds to the acidic TME to expose the dodecyl group on the surface of the expanded nanoparticles, facilitating their cytomembrane insertion. Subsequently, the protruding bisphosphonic acid group triggers continuous ion deposition to construct a mineralized barrier around the tumor, which blocks substance exchange between the tumor and surrounding normal tissues. The BINP-mediated blockade therapy displays tumor inhibition rates of 59.3% and 52.1% for subcutaneous and orthotopic osteosarcomas, respectively, compared with the Control group. In addition, the suppression of osteoclasts by the alendronate moiety alleviates bone dissolution and further inhibits pulmonary metastases. Hence, the BINP-initiated selective biomineralization provides a promising alternative for clinical osteosarcoma therapy.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
198. Prognostic Factors in High-Grade Osteosarcoma of theExtremities or Trunk: An Analysis of 1,702 Patients Treatedon Neoadjuvant Cooperative Osteosarcoma Study GroupProtocols.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2023-09-20
DOI :10.1200/JCO.22.02767
PURPOSE:To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS:A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS:Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival ≥ 40, 41.6%; < 40, 60.2%; = .012), tumor site (axial, 29.2%; limb, 61.7%; < .0001), and primary metastases (yes, 26.7%; no, 64.4%; < .0001), and for extremity osteosarcomas, also size (≥ one third, 52.5%; < one third, 66.7%; < .0001) and location within the limb (proximal, 49.3%; other, 63.9%; < .0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; < .0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; < .0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION:Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
打开PDF
登录
英汉
199. The Childhood Cancer Data Initiative: Using the Power of Data to Learn From and Improve Outcomes for Every Child and Young Adult With Pediatric Cancer.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2023-06-02
DOI :10.1200/JCO.22.02208
Data-driven basic, translational, and clinical research has resulted in improved outcomes for children, adolescents, and young adults (AYAs) with pediatric cancers. However, challenges in sharing data between institutions, particularly in research, prevent addressing substantial unmet needs in children and AYA patients diagnosed with certain pediatric cancers. Systematically collecting and sharing data from every child and AYA can enable greater understanding of pediatric cancers, improve survivorship, and accelerate development of new and more effective therapies. To accomplish this goal, the Childhood Cancer Data Initiative (CCDI) was launched in 2019 at the National Cancer Institute. CCDI is a collaborative community endeavor supported by a 10-year, $50-million (in US dollars) annual federal investment. CCDI aims to learn from every patient diagnosed with a pediatric cancer by designing and building a data ecosystem that facilitates data collection, sharing, and analysis for researchers, clinicians, and patients across the cancer community. For example, CCDI's Molecular Characterization Initiative provides comprehensive clinical molecular characterization for children and AYAs with newly diagnosed cancers. Through these efforts, the CCDI strives to provide clinical benefit to patients and improvements in diagnosis and care through data-focused research support and to build expandable, sustainable data resources and workflows to advance research well past the planned 10 years of the initiative. Importantly, if CCDI demonstrates the success of this model for pediatric cancers, similar approaches can be applied to adults, transforming both clinical research and treatment to improve outcomes for all patients with cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
200. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study.
BACKGROUND:Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. METHODS:This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m per day, capped at 24 mg per day, and etoposide (100 mg/m per day) plus ifosfamide (3000 mg/m per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274. FINDINGS:30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m combination group and two in the 14 mg/m combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m per day (with daily dose cap of 24 mg) and etoposide 100 mg/m per day plus ifosfamide 3000 mg/m per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred. INTERPRETATION:Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189). FUNDING:Eisai and Merck Sharp & Dohme.
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
跳转PDF
登录
英汉
201. Antibody-activation of connexin hemichannels in bone osteocytes with ATP release suppresses breast cancer and osteosarcoma malignancy.
期刊:Cell reports
日期:2024-06-17
DOI :10.1016/j.celrep.2024.114377
Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody's inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
跳转PDF
登录
英汉
202. Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.
期刊:The Lancet. Oncology
日期:2023-05-11
DOI :10.1016/S1470-2045(23)00154-7
BACKGROUND:Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. METHODS:We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. FINDINGS:Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. INTERPRETATION:Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. FUNDING:US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
203. Copper-Loaded Nanoheterojunction Enables Superb Orthotopic Osteosarcoma Therapy via Oxidative Stress and Cell Cuproptosis.
期刊:ACS nano
日期:2023-10-30
DOI :10.1021/acsnano.3c04903
Catalytic tumor therapy based on two-dimensional (2D) nanomaterials is a burgeoning and promising tumor therapeutic modality. However, the inefficient utilization and conversion of exogenous stimulation, single catalytic modality, and unsatisfactory therapeutic efficiency in the tumor microenvironment (TME) have seriously restricted their further application in tumor therapy. Herein, the heterogeneous carbon nitride-based nanoagent named T-HCN@CuMS was successfully developed, which dramatically improved the efficiency of the tumor therapeutic modality. Benefiting from the donor-acceptor (triazine-heptazine) structure within the heterogeneous carbon nitride nanosheets (HCN) and the construction of interplanar heterostructure with copper loaded metallic molybdenum bisulfide nanosheets (CuMS), T-HCN@CuMS presented a favorable photo-induced catalytic property to generate abundant reactive oxygen species (ROS) under near-infrared (NIR) light irradiation. Besides, the choice of CuMS simultaneously enabled this nanoagent to efficiently catalyze the Fenton-like reaction and trigger cell cuproptosis, a recently recognized regulated cell death mode characterized by imbalanced intracellular copper homeostasis and aggregation of lipoylated mitochondrial proteins. Moreover, upon surface modification with cRGD-PEG-DSPE, T-HCN@CuMS was prepared and endowed with improved dispersibility and αβ integrins targeting ability. In general, through the rational design, T-HCN@CuMS was facilely prepared and had achieved satisfactory antitumor and antimetastasis outcomes both and in a high-metastatic orthotopic osteosarcoma model. This strategy could offer an idea to treat malignant diseases based on 2D nanomaterials.
添加收藏
创建看单
引用
1区Q1影响因子: 28.1
打开PDF
登录
英汉
204. Wnt signaling and Loxl2 promote aggressive osteosarcoma.
期刊:Cell research
日期:2020-07-20
DOI :10.1038/s41422-020-0370-1
Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.
添加收藏
创建看单
引用
1区Q1影响因子: 26.8
英汉
205. A phosphorescent probe for in vivo imaging in the second near-infrared window.
期刊:Nature biomedical engineering
日期:2021-08-12
DOI :10.1038/s41551-021-00773-2
In the second near-infrared spectral window (NIR-II; with wavelengths of 1,000-1,700 nm), in vivo fluorescence imaging can take advantage of reduced tissue autofluorescence and lower light absorption and scattering by tissue. Here, we report the development and in vivo application of a NIR-II phosphorescent probe that has lifetimes of hundreds of microseconds and a Stokes shift of 430 nm. The probe is made of glutathione-capped copper-indium-selenium nanotubes, and in acidic environments (pH 5.5-6.5) switches from displaying fluorescence to phosphorescence. In xenograft models of osteosarcoma and breast cancer, intravenous or intratumoral injections of the probe enabled phosphorescence imaging at signal-to-background ratios, spatial resolutions and sensitivities higher than NIR-II fluorescence imaging with polymer-stabilized copper-indium-sulfide nanorods. Phosphorescence imaging may offer superior imaging performance for a range of biomedical uses.
添加收藏
创建看单
引用
1区Q1影响因子: 22.5
跳转PDF
登录
英汉
206. Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial.
期刊:JAMA oncology
日期:2024-12-01
DOI :10.1001/jamaoncol.2024.4381
Importance:The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines. Objective:To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma. Design, Setting, and Participants:The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock). Interventions:The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review. Main Outcomes and Measures:The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics. Results:A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm. Conclusions and Relevance:Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design. Trial Registration:ClinicalTrials.gov Identifier: NCT04154189.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
207. First case of osteosarcoma in a dinosaur: a multimodal diagnosis.
作者:Ekhtiari Seper , Chiba Kentaro , Popovic Snezana , Crowther Rhianne , Wohl Gregory , Kin On Wong Andy , Tanke Darren H , Dufault Danielle M , Geen Olivia D , Parasu Naveen , Crowther Mark A , Evans David C
作者:Liao Dan , Zhong Li , Yin Junqiang , Zeng Cuiling , Wang Xin , Huang Xingchuan , Chen Jinna , Zhang Hong , Zhang Ruhua , Guan Xin-Yuan , Shuai Xintao , Sui Jianhua , Gao Song , Deng Wuguo , Zeng Yi-Xin , Shen Jing-Nan , Chen Jian , Kang Tiebang
期刊:Nature cell biology
日期:2020-07-01
DOI :10.1038/s41556-020-0541-9
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
209. Versatile Polymer-Initiating Biomineralization for Tumor Blockade Therapy.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2022-03-30
DOI :10.1002/adma.202110094
Tumor blockade therapy is a promising penetration-independent antitumor modality, which effectively inhibits the exchange of nutrients, oxygen, and information between the tumor and surrounding microenvironments. However, the current blockade therapy strategies have limited antitumor efficacy due to defects of inadequate tumor obstruction, possible side effects, and short duration. For these reasons, a facilely synthesized versatile polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA) is developed to initiate the formation of biomineral shell around osteosarcoma as a potent physical barrier. The DSPE moiety shares a similar chemical structure with the cytomembrane, allowing the membrane insertion of DPA. The bisphosphonic acid groups in ALN attract ions to realize biomineralization around cells. After injection in the invasive osteosarcoma tissue, DPA inserts into the cytomembrane, induces continuous mineral deposition, and ultimately builds a physical barrier around the tumor. Meanwhile, ALN in DPA alleviates bone destruction by suppressing the activity of osteoclasts. Through hindering the exchange of necessary substances, the biomineralization coating inhibits the growth of primary osteosarcoma and pulmonary metastasis simultaneously. Therefore, the multifunctional polymer-initiating blockade therapy provides a promising modality for tumor inhibition in clinics with high efficacy and negligible side effects.
添加收藏
创建看单
引用
1区Q1影响因子: 17.3
英汉
210. Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.
期刊:Nature cell biology
日期:2020-06-01
DOI :10.1038/s41556-020-0522-z
Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
211. Photothermal Catalytic Reduction and Bone Tissue Engineering Towards a Three-in-One Therapy Strategy for Osteosarcoma.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2024-08-20
DOI :10.1002/adma.202408016
Osteosarcoma is one of the most dreadful bone neoplasms in young people, necessitating the development of innovative therapies that can effectively eliminate tumors while minimizing damage to limb function. An ideal therapeutic strategy should possess three essential capabilities: antitumor effects, tissue-protective properties, and the ability to enhance osteogenesis. In this study, self-assembled Ce-substituted molybdenum blue (CMB) nanowheel crystals are synthesized and loaded onto 3D-printed bioactive glass (CMB@BG) scaffolds to develop a unique three-in-one treatment approach for osteosarcoma. The CMB@BG scaffolds exhibit outstanding photothermally derived tumor ablation within the near-infrared-II window due to the surface plasmon resonance properties of the CMB nanowheel crystals. Furthermore, the photothermally synergistic catalytic effect of CMB promotes the rapid scavenging of reactive oxygen species caused by excessive heat, thereby suppressing inflammation and protecting surrounding tissues. The CMB@BG scaffolds possess pro-proliferation and pro-differentiation capabilities that efficiently accelerate bone regeneration within bone defects. Altogether, the CMB@BG scaffolds that combine highly efficient tumor ablation, tissue protection based on anti-inflammatory mechanisms, and enhanced osteogenic ability are likely to be a point-to-point solution for the comprehensive therapeutic needs of osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
212. Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma.
期刊:Science translational medicine
日期:2024-05-29
DOI :10.1126/scitranslmed.adg9814
T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
打开PDF
登录
英汉
213. Time-Sequential and Multi-Functional 3D Printed MgO/PLGA Scaffold Developed as a Novel Biodegradable and Bioactive Bone Substitute for Challenging Postsurgical Osteosarcoma Treatment.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-12-24
DOI :10.1002/adma.202308875
Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti-tumor, anti-bacterial, and long-lasting osteogenesis. Herein, multi-functional bioactive scaffolds with time-sequential functions of preventing tumor recurrence, inhibiting bacterial infection, and promoting bone defect repair are designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO)/poly (lactide-co-glycolide) is prepared by low-temperature 3D printing for controllable releasing magnesium ions (Mg) and reactive oxygen species in a time-sequential manner. The scaffold with 20 wt% MgO (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (HO) release for the first 3 weeks, and long-lasting Mg release for 12 weeks. The released HO initiates chemodynamic therapy to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg subsequently enhances bone repair by activating the Wnt3a/GSK-3β/β-catenin signaling pathway to promote osteogenic differentiation of bone marrow mesenchymal stem cells and create osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi-functional 20MP scaffold demonstrates time-sequential therapeutic properties as an innovative strategy for OS-associated bone defect treatment.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
214. Cabozantinib: a new perspective for advanced bone sarcoma.
作者:Fagioli Franca , Tirtei Elisa
期刊:The Lancet. Oncology
日期:2020-02-17
DOI :10.1016/S1470-2045(20)30004-8
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
215. Antiangiogenic agents combined with systemic chemotherapy in refractory osteosarcoma.
作者:Rutkowski Piotr
期刊:The Lancet. Oncology
日期:2021-08-17
DOI :10.1016/S1470-2045(21)00422-8
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
216. Extracellular-vesicle-packaged S100A11 from osteosarcoma cells mediates lung premetastatic niche formation by recruiting gMDSCs.
期刊:Cell reports
日期:2024-02-10
DOI :10.1016/j.celrep.2024.113751
The premetastatic niche (PMN) contributes to lung-specific metastatic tropism in osteosarcoma. However, the crosstalk between primary tumor cells and lung stromal cells is not clearly defined. Here, we dissect the composition of immune cells in the lung PMN and identify granulocytic myeloid-derived suppressor cell (gMDSC) infiltration as positively associated with immunosuppressive PMN formation and tumor cell colonization. Osteosarcoma-cell-derived extracellular vesicles (EVs) activate lung interstitial macrophages to initiate the influx of gMDSCs via secretion of the chemokine CXCL2. Proteomic profiling of EVs reveals that EV-packaged S100A11 stimulates the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in macrophages by interacting with USP9X. High level of S100A11 expression or circulating gMDSCs correlates with the presentation of lung metastasis and poor prognosis in osteosarcoma patients. In summary, we identify a key role of tumor-derived EVs in lung PMN formation, providing potential strategies for monitoring or preventing lung metastasis in osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
英汉
217. A Gas/phototheranostic Nanocomposite Integrates NIR-II-Peak Absorbing Aza-BODIPY with Thermal-Sensitive Nitric Oxide Donor for Atraumatic Osteosarcoma Therapy.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-06-02
DOI :10.1002/adma.202301901
Photothermal therapy (PTT) has received increasing interest in cancer therapeutics owing to its excellent efficacy and controllability. However, there are two major limitations in PTT applications, which are the tissue penetration depth of lasers within the absorption range of photothermal agents and the unavoidable tissue empyrosis induced by high-energy lasers. Herein, a gas/phototheranostic nanocomposite (NA1020-NO@PLX) is engineered that integrates the second near-infrared-peak (NIR-II-peak) absorbing aza-boron-dipyrromethenes (aza-BODIPY,NA1020) with the thermal-sensitive nitric oxide (NO) donor (S-nitroso-N-acetylpenicillamine, SNAP). An enhanced intramolecular charge transfer mechanism is proposed to achieve the NIR-II-peak absorbance (λ = 1020 nm) on NA1020, thereby obtaining its deep tissue penetration depth. The NA1020 exhibits a remarkable photothermal conversion, making it feasible for the deep-tissue orthotopic osteosarcoma therapy and providing favorable NIR-II emission to precisely pinpoint the tumor for a visible PTT process. The simultaneously investigated atraumatic therapeutic process with an enhanced cell apoptosis mechanism indicates the feasibility of the synergistic NO/low-temperature PTT for osteosarcoma. Herein, this gas/phototheranostic strategy optimizes the existing PTT to present a repeatable and atraumatic photothermal therapeutic process for deep-tissue tumors, validating its potential clinical applications.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
218. Flashback Foreword: Prognostic Factors in Osteosarcoma.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2023-09-20
DOI :10.1200/JCO.22.02860
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
跳转PDF
登录
英汉
219. Identification of a class of non-conventional ER-stress-response-derived immunogenic peptides.
期刊:Cell reports
日期:2021-07-06
DOI :10.1016/j.celrep.2021.109312
Efforts to overcome resistance to immune checkpoint blockade therapy have focused on vaccination strategies using neoepitopes, although they cannot be applied on a large scale due to the "private" nature of cancer mutations. Here, we show that infection of tumor cells with Salmonella induces the opening of membrane hemichannels and the extracellular release of proteasome-generated peptides by the exacerbation of endoplasmic reticulum (ER) stress. Peptides released by cancer cells foster an antitumor response in vivo, both in mice bearing B16F10 melanomas and in dogs suffering from osteosarcoma. Mass spectrometry analysis on the supernatant of human melanoma cells revealed 12 peptides capable of priming healthy-donor CD8 T cells that recognize and kill human melanoma cells in vitro and when xenotransplanted in vivo. Hence, we identified a class of shared tumor antigens that are generated in ER-stressed cells, such as tumor cells, that do not induce tolerance and are not presented by healthy cells.
添加收藏
创建看单
引用
1区Q1影响因子: 27.4
打开PDF
登录
英汉
220. KERS-Inspired Nanostructured Mineral Coatings Boost IFN-γ mRNA Therapeutic Index for Antitumor Immunotherapy.
期刊:Advanced materials (Deerfield Beach, Fla.)
日期:2023-10-27
DOI :10.1002/adma.202304296
Tumor-associated macrophage (TAM) reprogramming is a promising therapeutic approach for cancer immunotherapy; however, its efficacy remains modest due to the low bioactivity of the recombinant cytokines used for TAM reprogramming. mRNA therapeutics are capable of generating fully functional proteins for various therapeutic purposes but accused for its poor sustainability. Inspired by kinetic energy recovery systems (KERS) in hybrid vehicles, a cytokine efficacy recovery system (CERS) is designed to substantially augment the therapeutic index of mRNA-based tumor immunotherapy via a "capture and stabilize" mechanism exerted by a nanostructured mineral coating carrying therapeutic cytokine mRNA. CERS remarkably recycles nearly 40% expressed cytokines by capturing them onto the mineral coating to extend its therapeutic timeframe, further polarizing the macrophages to strengthen their tumoricidal activity and activate adaptive immunity against tumors. Notably, interferon-γ (IFN-γ) produced by CERS exhibits ≈42-fold higher biological activity than recombinant IFN-γ, remarkably decreasing the required IFN-γ dosage for TAM reprogramming. In tumor-bearing mice, IFN-γ cmRNA@CERS effectively polarizes TAMs to inhibit osteosarcoma progression. When combined with the PD-L1 monoclonal antibody, IFN-γ cmRNA@CERS significantly boosts antitumor immune responses, and substantially prevents malignant lung metastases. Thus, CERS-mediated mRNA delivery represents a promising strategy to boost antitumor immunity for tumor treatment.
添加收藏
创建看单
引用
1区Q1影响因子: 98.4
英汉
221. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial.
期刊:Lancet (London, England)
日期:2024-11-12
DOI :10.1016/S0140-6736(24)01812-9
BACKGROUND:Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival. METHODS:We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1-14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab (200 mg intravenously every 3 weeks) was administered as three neoadjuvant cycles (before, during, and after radiotherapy) and 14 or less adjuvant cycles. Primary endpoint was disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323). FINDINGS:Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39-0·96). The 2-year disease-free survival increased by 15% with addition of pembrolizumab: 52% (90% CI 42-64) and 67% (90% CI 58-78) for the control and experimental groups, respectively. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat patient population (HR 0·61 [90% CI 0·39-0·95]). Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%). INTERPRETATION:Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients. FUNDING:Stand Up to Cancer and Merck Sharp & Dohme.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
222. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.
期刊:The Lancet. Oncology
日期:2022-08-04
DOI :10.1016/S1470-2045(22)00392-8
BACKGROUND:Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS:In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS:Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION:The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING:AstraZeneca.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
跳转PDF
登录
英汉
223. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial.
作者:Davis Kara L , Fox Elizabeth , Merchant Melinda S , Reid Joel M , Kudgus Rachel A , Liu Xiaowei , Minard Charles G , Voss Stephan , Berg Stacey L , Weigel Brenda J , Mackall Crystal L
期刊:The Lancet. Oncology
日期:2020-03-17
DOI :10.1016/S1470-2045(20)30023-1
BACKGROUND:Immune checkpoint inhibitors targeting PD-1 have shown clinical benefit in adults with cancer, but data on these drugs in children are scarce. We did a phase 1-2 study of nivolumab, a PD-1 blocking monoclonal antibody, to determine its safety, pharmacokinetics, and antitumour activity in children and young adults with recurrent or refractory non-CNS solid tumours or lymphoma. METHODS:We did a multicentre, open-label, single-arm, dose-confirmation and dose-expansion, phase 1-2 trial in 23 hospitals in the USA. Eligible patients for part A (dose-confirmation phase) of the study were aged 1-18 years with solid tumours with measurable or evaluable disease (by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) regardless of histology. Eligible patients for part B (dose-expansion phase) were aged 1-30 years with measurable disease (by RECIST criteria) in the following disease cohorts: rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in part A and were given nivolumab 3 mg/kg intravenously over 60 min on days 1 and 15 of a 28-day cycle in a rolling 6 study design with de-escalation upon dose-limiting toxicities to establish the recommended phase 2 dose. Patients in part B were given the recommended phase 2 dose. The primary outcomes were the tolerability, systemic exposure, maximum tolerated dose, and the antitumour activity of nivolumab at the adult recommended dose in children and young adults. This trial is registered with ClinicalTrials.gov, NCT02304458, with follow-up ongoing and is closed to new participants. FINDINGS:85 patients were enrolled between Feb 22, 2015, and Dec 31, 2018, and 75 patients were fully evaluable for toxicity. Median follow-up was 30 days (IQR 27-83). In part A, 13 patients were enrolled and 12 were evaluable for toxicity. There were no dose de-escalations or dose-limiting toxicities and nivolumab 3 mg/kg was confirmed as the paediatric recommended phase 2. 72 patients were enrolled in part B and 63 were evaluable for toxicity. Five (7%) patients in part B had dose-limiting toxicities. The most common overall toxicity was anaemia (35 [47%] of 75 patients; five patients had grade 3 or grade 4) and non-haematological toxicity was fatigue (28 [37%] patients; none had grade 3 or grade 4). Responses were observed in patients with lymphoma (three [30%] of ten with Hodgkin lymphoma and one [10%] of ten with non-Hodgkin lymphoma; all responders had PD-L1 expression). Objective responses were not observed in other tumour types. INTERPRETATION:Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in lymphoma. Nivolumab showed no significant single-agent activity in the common paediatric solid tumours. This study defines the recommended phase 2 dose and establishes a favourable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer. FUNDING:Bristol-Myers Squibb, Children's Oncology Group, National Institutes of Health, Cookies for Kids Cancer Foundation.
添加收藏
创建看单
引用
1区Q1影响因子: 15.8
英汉
224. Mitochondria-Targeting Polymer Micelle of Dichloroacetate Induced Pyroptosis to Enhance Osteosarcoma Immunotherapy.
期刊:ACS nano
日期:2022-06-23
DOI :10.1021/acsnano.2c00192
Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(-oxide-,-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.
添加收藏
创建看单
引用
1区Q1影响因子: 27.7
跳转PDF
登录
英汉
225. Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping.
期刊:Nature immunology
日期:2024-07-02
DOI :10.1038/s41590-024-01884-z
The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56 state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56 state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
跳转PDF
登录
英汉
226. Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2023-01-20
DOI :10.1200/JCO.22.02423
PURPOSE:For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. METHODS:Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status. RESULTS:From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m. CONCLUSION:Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
英汉
227. Extraskeletal osteosarcoma of primary retroperitoneal origin.
期刊:The Lancet. Oncology
日期:2023-06-01
DOI :10.1016/S1470-2045(23)00155-9
添加收藏
创建看单
引用
1区Q1影响因子: 81.1
英汉
228. AKT inhibition associated with improved OS.
期刊:Nature reviews. Clinical oncology
日期:2022-09-01
DOI :10.1038/s41571-022-00662-w
添加收藏
创建看单
引用
1区Q1影响因子: 12.9
英汉
229. Dissolution of oncofusion transcription factor condensates for cancer therapy.
期刊:Nature chemical biology
日期:2023-07-03
DOI :10.1038/s41589-023-01376-5
Cancer-associated chromosomal rearrangements can result in the expression of numerous pathogenic fusion proteins. The mechanisms by which fusion proteins contribute to oncogenesis are largely unknown, and effective therapies for fusion-associated cancers are lacking. Here we comprehensively scrutinized fusion proteins found in various cancers. We found that many fusion proteins are composed of phase separation-prone domains (PSs) and DNA-binding domains (DBDs), and these fusions have strong correlations with aberrant gene expression patterns. Furthermore, we established a high-throughput screening method, named DropScan, to screen drugs capable of modulating aberrant condensates. One of the drugs identified via DropScan, LY2835219, effectively dissolved condensates in reporter cell lines expressing Ewing sarcoma fusions and partially rescued the abnormal expression of target genes. Our results indicate that aberrant phase separation is likely a common mechanism for these PS-DBD fusion-related cancers and suggest that modulating aberrant phase separation is a potential route to treat these diseases.
Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.
添加收藏
创建看单
引用
1区Q1影响因子: 41.6
打开PDF
登录
英汉
232. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.
期刊:The Lancet. Oncology
日期:2020-02-17
DOI :10.1016/S1470-2045(19)30825-3
BACKGROUND:Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS:We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS:Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION:Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING:Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.
添加收藏
创建看单
引用
1区Q1影响因子: 42.1
英汉
233. Pediatric Leukemia Roadmaps Are a Guide for Positive Metastatic Bone Sarcoma Trials.
期刊:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
日期:2024-06-06
DOI :10.1200/JCO.23.02717
ALL cures require many MRD therapies. This strategy should drive experiments and trials in metastatic bone sarcomas.
添加收藏
创建看单
引用
1区Q1影响因子: 22.5
跳转PDF
登录
英汉
234. Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.
作者:Mirabello Lisa , Zhu Bin , Koster Roelof , Karlins Eric , Dean Michael , Yeager Meredith , Gianferante Matthew , Spector Logan G , Morton Lindsay M , Karyadi Danielle , Robison Leslie L , Armstrong Gregory T , Bhatia Smita , Song Lei , Pankratz Nathan , Pinheiro Maisa , Gastier-Foster Julie M , Gorlick Richard , de Toledo Silvia Regina Caminada , Petrilli Antonio S , Patino-Garcia Ana , Lecanda Fernando , Gutierrez-Jimeno Miriam , Serra Massimo , Hattinger Claudia , Picci Piero , Scotlandi Katia , Flanagan Adrienne M , Tirabosco Roberto , Amary Maria Fernanda , Kurucu Nilgün , Ilhan Inci Ergurhan , Ballinger Mandy L , Thomas David M , Barkauskas Donald A , Mejia-Baltodano Gerardo , Valverde Patricia , Hicks Belynda D , Zhu Bin , Wang Mingyi , Hutchinson Amy A , Tucker Margaret , Sampson Joshua , Landi Maria T , Freedman Neal D , Gapstur Susan , Carter Brian , Hoover Robert N , Chanock Stephen J , Savage Sharon A
期刊:JAMA oncology
日期:2020-05-01
DOI :10.1001/jamaoncol.2020.0197
Importance:Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective:To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants:Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures:The frequency of rare pathogenic or likely pathogenic genetic variants. Results:Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance:In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
英汉
235. GD2-CAR CAR T cells in patients with osteosarcoma and neuroblastoma-it's not only the T cells that matter.
期刊:Cancer cell
日期:2023-12-21
DOI :10.1016/j.ccell.2023.11.012
GD2-CAR T cells were safe and anti-tumor responses were limited. In this issue of Cancer Cell, Kaczanowska et al. find that apheresis products and peripheral blood at baseline contained significantly higher proportions of CXCR3+ monocytes in good expanders. CXCR3+ monocytes may influence CAR T cell function.
添加收藏
创建看单
引用
1区Q1影响因子: 11.7
跳转PDF
登录
英汉
236. Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma.
期刊:Science advances
日期:2023-11-22
DOI :10.1126/sciadv.adi0889
Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.
添加收藏
创建看单
引用
1区Q1影响因子: 12.9
英汉
237. Processing for destruction.
作者:Erb Michael A
期刊:Nature chemical biology
日期:2020-01-01
DOI :10.1038/s41589-019-0428-x
添加收藏
创建看单
引用
1区Q1影响因子: 44.7
英汉
238. Inherited genome instability.
期刊:Science (New York, N.Y.)
日期:2025-01-02
DOI :10.1126/science.adu6125
Germline structural variants are a risk factor for pediatric extracranial solid tumors.
添加收藏
创建看单
引用
1区Q1影响因子: 48.8
跳转PDF
登录
英汉
239. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.
期刊:Cancer cell
日期:2023-12-21
DOI :10.1016/j.ccell.2023.11.011
Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3 monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3 classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.
添加收藏
创建看单
引用
1区Q1影响因子: 96.2
英汉
240. New Horizons in the Treatment of Osteosarcoma.
作者:Meltzer Paul S , Helman Lee J
期刊:The New England journal of medicine
日期:2021-11-25
DOI :10.1056/NEJMra2103423
添加收藏
创建看单
引用
1区Q1影响因子: 76.9
英汉
241. Author Correction: Osteosarcoma.
期刊:Nature reviews. Disease primers
日期:2022-12-30
DOI :10.1038/s41572-022-00416-z
添加收藏
创建看单
引用
1区Q1影响因子: 7.5
英汉
242. Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.
期刊:Cell reports
日期:2023-09-19
DOI :10.1016/j.celrep.2023.113147
Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.
添加收藏
创建看单
引用
1区Q1影响因子: 76.9
英汉
243. Osteosarcoma.
期刊:Nature reviews. Disease primers
日期:2022-12-08
DOI :10.1038/s41572-022-00411-4
添加收藏
创建看单
引用
1区Q1影响因子: 81.1
打开PDF
登录
英汉
244. Advancing therapy for osteosarcoma.
作者:Gill Jonathan , Gorlick Richard
期刊:Nature reviews. Clinical oncology
日期:2021-06-15
DOI :10.1038/s41571-021-00519-8
Improving the survival of patients with osteosarcoma has long proved challenging, although the treatment of this disease is on the precipice of advancement. The increasing feasibility of molecular profiling together with the creation of both robust model systems and large, well-annotated tissue banks has led to an increased understanding of osteosarcoma biology. The historical invariability of survival outcomes and the limited number of agents known to be active in the treatment of this disease facilitate clinical trials designed to identify efficacious novel therapies using small cohorts of patients. In addition, trial designs will increasingly consider the genetic background of the tumour through biomarker-based patient selection, thereby enriching for clinical activity. Indeed, osteosarcoma cells are known to express a number of surface proteins that might be of therapeutic relevance, including B7-H3, GD2 and HER2, which can be targeted using antibody-drug conjugates and/or adoptive cell therapies. In addition, immune-checkpoint inhibition might augment the latter approach by helping to overcome the immunosuppressive tumour microenvironment. In this Review, we provide a brief overview of current osteosarcoma therapy before focusing on the biological insights from the molecular profiling and preclinical modelling studies that have opened new therapeutic opportunities in this disease.
添加收藏
创建看单
引用
1区Q1影响因子: 76.9
英汉
245. Osteosarcoma.
期刊:Nature reviews. Disease primers
日期:2022-12-08
DOI :10.1038/s41572-022-00409-y
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
添加收藏
创建看单
引用
3区Q2影响因子: 3
英汉
246. DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications.
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents which has the survival rate of 20% in its advanced stages. Osteosarcomas are mostly resistance to our common treatments. DNA damage response (DDR) is a specialized multistep process containing abundant proteins which are necessary for the survival of any cell and organism. DDR machinery detects a diversity of DNA lesions and inhibits the cell cycle progression if these lesions are not repairable. DDR is involved in aging, age-related diseases, and cancer. In recent years, DDR inhibitors have gained the attention of researches due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy. In this regard, we tried to gather a great body of evidence about the role of DDR ingredients in osteosarcoma's initiation/progression, prognosis, and treatment.
添加收藏
创建看单
引用
4区Q2影响因子: 3.3
英汉
247. The emerging role of lncRNAs in the regulation of osteosarcoma stem cells.
作者:Song X-J , Bi M-C , Zhu Q-S , Liu X-L
期刊:European review for medical and pharmacological sciences
日期:2022-02-01
DOI :10.26355/eurrev_202202_28006
OBJECTIVE:Osteosarcoma is a common bone sarcoma that often occurs in childhood and adolescence. In recent years, the efficacy of osteosarcoma treatments has been improved by adjuvant chemotherapies and surgical approaches. However, poor prognosis often occurs among osteosarcoma patients due to recurrence, metastasis, or drug resistance problems. Cancer stem cells (CSCs), a specific type of tumor malignant cells with stem cell-like properties, have been reported to be responsible for tumor origination, aggression, metastasis, recurrence, and drug resistance. CSCs have been identified in osteosarcomas treatment, which exhibits self-renewal, multi-potency, and enhanced drug resistance. Therefore, in the present narrative review, we intend to summarize the role of lncRNAs in regulating CSCs and their effectiveness in the treatment of osteosarcoma. MATERIALS AND METHODS:The databases PubMed (Medline), Web of Science, Embase, Scopus, and Cochrane Library, were used for the presented study. The keywords we used to complete our search are 'lncRNA', 'Stem cell', and 'osteosarcoma'. A total of over 800 relevant articles, with a time limit from 2010 to 2021, were identified according to search strategy. Duplicate records and review articles were excluded by their titles and abstracts. Finally, we found about 80 articles matching our inclusion criteria, which included about 13 relevant studies focusing on both the mechanism and effectiveness of osteosarcomas treatment among osteosarcoma patients. RESULTS:CD133, CD117, ALDH, and Stro-1 are validated as the stem cell biomarkers in osteosarcoma CSCs. Accumulating evidence has revealed that lncRNAs, containing HIF2PUT, SOX2-OT, MALAT1, THOR, B4GALT1-AS1, H19, PVT1, FER1L4, LINK-A, DANCR, and DLX6-AS1, play a potential role in regulating CSCs in osteosarcoma. The drug resistance, inhibition of the relapse, and metastasis in osteosarcoma could be avoided via regulating lncRNAs of targeting CSCs. CONCLUSIONS:Multiple lncRNAs regulate CSCs in osteosarcoma via various molecular mechanisms. This review demonstrated that the method of eliminating CSCs by targeting these lncRNAs is a safe, effective, and a well-tolerated way for osteosarcoma patients, which shows a broad research prospect in tumor diagnoses and therapies. However, this method should be further demonstrated by better animal models and more clinical experiments.
添加收藏
创建看单
引用
4区Q4影响因子: 1.2
跳转PDF
登录
英汉
248. Metachronous Osteosarcoma, A Differential Diagnosis to be Considered in Children With Osteosarcoma: A Review of Literature and a Case From Our Center.
期刊:Journal of pediatric hematology/oncology
日期:2022-10-17
DOI :10.1097/MPH.0000000000002560
Metachronous osteosarcomas (MOS) are currently defined as tumors that arise in a way and site unusual for typical metastasis. In this article, we reviewed the recent literature on the occurrence of metachronous osteosarcoma and presented a case from our center. Our patient, a 10-year-old girl, presented with metachronous osteoblastic osteosarcoma of the left distal femur ∼5 years after the successful treatment for osteosarcoma of the right distal femur. Even after several relapses, complete remission (CR) was achieved after the first osteosarcoma and after the metachronous osteosarcoma. The literature research revealed that metachronous osteosarcoma occurs in 3.4 to 5.4% of osteosarcoma patients. The time interval between the diagnosis of the initial osteosarcoma and the metachronous tumor ranged from 0.2 to 14.3 years (median 2.5 y). MOS appears to have differences in localization and metastatic spread, as well as a different survival pattern compared with primary osteosarcoma and osteosarcoma recurrence. Survival (median 4.3 y, range 0 to 24.6 y) appears to be associated with the time interval to diagnosis of MOS. In particular, early MOS (<24 mo after primary diagnosis) seem to have a poorer prognosis. Therefore, the occurrence of MOS at oncological unusual sites should be considered as a differential diagnosis in osteosarcoma survivors.
添加收藏
创建看单
引用
4区Q4影响因子: 1.2
英汉
249. Monocytes, Macrophages, and Osteoclasts in Osteosarcoma.
作者:Kelleher Fergal C , O'Sullivan Hazel
期刊:Journal of adolescent and young adult oncology
日期:2017-03-06
DOI :10.1089/jayao.2016.0078
Macrophages appear to have a fundamental role in the pathogenesis of osteosarcoma. These highly diverse plastic cells are subdivided into classical or inflammatory macrophages known as M1 and alternative macrophages, which decrease inflammation and are reparative, called M2. Although primary and metastatic osteosarcomas are infiltrated with M2 macrophages, targeting the M1 macrophages with the immune adjuvant muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) has been the greatest recent therapeutic advance in osteosarcoma. This discrepancy between the presence of M2 and activation of M1 macrophages is intriguing and is likely explained either by the plasticity of M1 and M2 macrophages or nonclassical patrolling monocytes (PMos). To date, MTP-PE has been approved in combination with chemotherapy for nonmetastatic osteosarcoma, but its use in metastatic tumors has not been investigated. In this review, we focus on macrophages, monocytes, and osteoclasts, their role in osteosarcoma, and the potential for targeting these cells in this disease.
添加收藏
创建看单
引用
跳转PDF
登录
英汉
250. Targeting WNT5B and WNT10B in osteosarcoma.
期刊:Oncotarget
日期:2024-08-02
DOI :10.18632/oncotarget.28617
WNT signaling regulates osteosarcoma proliferation. However, there is controversy in the field of osteosarcoma as to whether WNT signaling is pro- or anti-tumorigenic. WNT-targeting therapeutics, both activators and inhibitors, are compared. WNT5B, a β-catenin-independent ligand, and WNT10B, a β-catenin-dependent WNT ligand, are each expressed in osteosarcomas, but they are not expressed in the same tumors. Furthermore, WNT10B and WNT5B regulate different histological subtypes of osteosarcomas. Using WNT signaling modulators as therapeutics may depend on the WNT ligand and/or the activated signaling pathway.
添加收藏
创建看单
引用
1区Q1影响因子: 72.5
英汉
251. Translational biology of osteosarcoma.
作者:Kansara Maya , Teng Michele W , Smyth Mark J , Thomas David M
期刊:Nature reviews. Cancer
日期:2014-10-16
DOI :10.1038/nrc3838
For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.
添加收藏
创建看单
引用
3区Q1影响因子: 4.9
打开PDF
登录
英汉
252. Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy.
期刊:International journal of molecular sciences
日期:2020-07-23
DOI :10.3390/ijms21155207
Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
添加收藏
创建看单
引用
2区Q2影响因子: 5.1
打开PDF
登录
英汉
253. The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem.
Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.
添加收藏
创建看单
引用
1区Q1影响因子: 9.1
打开PDF
登录
英汉
254. Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs.
作者:Chen Chenglong , Xie Lu , Ren Tingting , Huang Yi , Xu Jie , Guo Wei
期刊:Cancer letters
日期:2020-12-23
DOI :10.1016/j.canlet.2020.12.024
Osteosarcoma (OS) is the most common primary malignancy of the bone and has a high propensity for local invasion and metastasis. Although combining surgery with chemotherapy has immensely improved the outcomes of osteosarcoma patients, the prognosis of metastatic or recurrent osteosarcomas is still unsatisfactory. Immunotherapy has proven to be a promising therapeutic strategy against human malignancies and improved understanding of the immune response to OS, and biomarker development has increased the number of patients who benefit from immunotherapies in recent years. Here, we review recent advances in immunotherapy in osteosarcoma and discuss the mechanisms and status of immunotherapies in both preclinical and clinical trials as well as future therapies on the horizon. These advances may pave the way for novel treatments requisite for patients with osteosarcoma in need of new therapies.
添加收藏
创建看单
引用
1区Q1影响因子: 503.1
跳转PDF
登录
英汉
255. Defeating lethal cancer: Interrupting the ecologic and evolutionary basis of death from malignancy.
期刊:CA: a cancer journal for clinicians
日期:2025-03-09
DOI :10.3322/caac.70000
Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved cancer survival, globally, there is an increased incidence in cancer-related deaths. Although each patient and each tumor is wholly unique, the tipping point to incurable disease is common across all patients: the dual capacity for cancers to metastasize and resist systemic treatment. The discovery of genetic mutations and epigenetic variation that emerges during cancer progression highlights that evolutionary and ecology principles can be used to understand how cancer evolves to a lethal phenotype. By applying such an eco-evolutionary framework, the authors reinterpret our understanding of the metastatic process as one of an ecologic invasion and define the eco-evolutionary paths of evolving therapy resistance. With this understanding, the authors draw from successful strategies optimized in evolutionary ecology to define strategic interventions with the goal of altering the evolutionary trajectory of lethal cancer. Ultimately, studying, understanding, and treating cancer using evolutionary ecology principles provides an opportunity to improve the lives of patients with cancer.