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Tenascin-C induced signaling in cancer. Orend Gertraud,Chiquet-Ehrismann Ruth Cancer letters Tenascin-C is an adhesion modulatory extracellular matrix molecule that is highly expressed in the microenvironment of most solid tumors. High tenascin-C expression reduces the prognosis of disease-free survival in patients with some cancers. The possible role of tenascin-C in tumor initiation and progression is addressed with emphasis on underlying signaling mechanisms. How tenascin-C affects malignant transformation, uncontrolled proliferation, angiogenesis, metastasis and escape from tumor immunosurveillance is summarized. Finally, we discuss how the phenotypes of tenascin-C knock-out mice may help define the roles of tenascin-C in tumorigenesis and how this knowledge could be applied to cancer therapy. 10.1016/j.canlet.2006.02.017
Plastin 1 drives metastasis of colorectal cancer through the IQGAP1/Rac1/ERK pathway. Zhang Tongtong,Wang Zheng,Liu Yanjun,Huo Yongxu,Liu Hongtao,Xu Chenxin,Mao Rui,Zhu Yifang,Liu Lei,Wei Danfeng,Liu Guanzhi,Pan Biran,Tang Yan,Zhou Zheng,Yang Chunlei,Guo Yuanbiao Cancer science Tumor metastasis is the dominant cause of death in colorectal cancer (CRC) patients, and it often involves dysregulation of various cytoskeletal proteins. Plastin 1 (PLS1) is an actin-bundling protein that has been implicated in the structure of intestinal epithelial microvilli; however, its role in CRC metastasis has not yet been determined. In this study, we demonstrated that PLS1 is highly expressed in 33.3% (45/135) of CRC patients and is correlated with lymph node metastasis and poor survival. In in vitro and in vivo experiments, PLS1 induced the migration and invasion of CRC cells and the metastases to the liver and lung in mice. Moreover, the expressions of key factors for CRC metastases, matrix metalloproteinase (MMP) 9 and 2, were enhanced by PLS1, which was dependent on phosphorylating ERK1/2 activated by IQGAP1/Rac1 signaling. The connection between these signals and PLS1 was further confirmed in CRC tissues of patients and the metastatic nodules from a mouse model. These findings suggest that PLS1 promotes CRC metastasis through the IQGAP1/Rac1/ERK pathway. Targeting PLS1 may provide a potential approach to inhibit the metastasis of CRC cells. 10.1111/cas.14438
Tumor-derived tenascin-C promotes the epithelial-mesenchymal transition in colorectal cancer cells. Takahashi Yusuke,Sawada Genta,Kurashige Junji,Matsumura Tae,Uchi Ryutaro,Ueo Hiroki,Ishibashi Masahisa,Takano Yuki,Akiyoshi Sayuri,Iwaya Takeshi,Eguchi Hidetoshi,Sudo Tomoya,Sugimachi Keishi,Yamamoto Hirofumi,Doki Yuichiro,Mori Masaki,Mimori Koshi Anticancer research BACKGROUND:Tenascin-C (TNC) is an extracellular matrix glycoprotein, usually derived from myofibroblasts in the cancer microenvironment. Recently, however, the significance of tumor-derived TNC in initiation of cancer metastasis was disclosed. We investigated the clinical significance of cancer-derived TNC in colorectal cancer (CRC) cases. MATERIALS AND METHODS:TNC expression in 170 cases of CRC was analyzed by quantitative real-time polymerase chain reaction (PCR). In addition, gene expression arrays using purely-separated cancer tissues of another 86 cases was performed and the functional implications of cancer-specific TNC were investigated. RESULTS:The expression of TNC mRNA was significantly higher in CRC tissues than in the corresponding normal tissues. Cancer cell-specific TNC expression was a significant prognostic factor in CRC cases. Moreover, cancer cell-derived TNC was associated with the epithelial-mesenchymal transition (EMT) signature. CONCLUSION:Cancer cell-derived TNC promotes cancer invasiveness via EMT regulation, and not cancer tissue TNC but cancer cell-specific TNC is a novel indicator of poor prognosis.
Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Oskarsson Thordur,Acharyya Swarnali,Zhang Xiang H-F,Vanharanta Sakari,Tavazoie Sohail F,Morris Patrick G,Downey Robert J,Manova-Todorova Katia,Brogi Edi,Massagué Joan Nature medicine We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche. 10.1038/nm.2379
Metabolic reprogramming-based characterization of circulating tumor cells in prostate cancer. Chen Jing,Cao Shunwang,Situ Bo,Zhong Juan,Hu Yanwei,Li Shufen,Huang Jinlan,Xu Jiasen,Wu Shiyang,Lin Jinduan,Zhao Qianwen,Cai Zhen,Zheng Lei,Wang Qian Journal of experimental & clinical cancer research : CR BACKGROUND:Circulating tumor cells (CTCs), an advantageous target of liquid biopsy, is an important biomarker for the prognosis and monitoring of cancer. Currently, detection techniques for CTCs are mainly based on the physical and/or epithelial characteristics of tumor cells. However, biofunctional activity markers that can indicate the high metastatic capacity of CTCs are lacking. METHODS:Functional microarray, quantitative real-time polymerase chain reaction, and Western blot were used on five prostate cancer cell lines with different metastatic capacities to identify the metastasis-related metabolic genes. The identified genes were detected in the CTCs of 64 clinical samples using the RNA in situ hybridization. A multi-criteria weighted model was used to determine the optimal metabolic markers for the CTCs test. Based on five fluorescent signals targeting DAPI, CD45, metabolic, epithelial (EpCAM/CKs), and mesenchymal (Vimentin/Twist) markers, the filtration-enriched CTCs were classified as GMCTCs/GMCTCs (metabolic types) or E-CTCs/H-CTCs/M-CTCs (EMT types). Correlation analysis and ROC curve were conducted on 54 prostate cancer samples to evaluate the clinical significance of CTCs subtypes. RESULTS:Eight metastasis-related metabolic genes were identified, including HK2, PDP2, G6PD, PGK1, PHKA1, PYGL, PDK1, and PKM2. Among them, PGK1 and G6PD were determined as optimal glucose metabolic (GM) markers for CTCs. GMCTCs (marked by PGK1/G6PD) were detectable in 64.8% (35/54) of prostate cancer patients, accounting for 46.5% (134/288) of total CTCs. An increased GMCTCs level was associated with advanced tumor stage and metastasis (P <  0.05). In the discrimination of cancer metastasis from non-metastasis, GMCTCs presented a higher AUC of the ROC curve (0.780) compared with the EMT CTCs subtypes (E-CTCs 0.729, H-CTCs 0.741, and M-CTCs 0.648). A triple tPSA-Gleason-GMCTCs marker increased the AUC to 0.904, which was better than that of the tPSA-Gleason-H-CTCs marker (0.874). CONCLUSIONS:The metabolic marker (PGK1/G6PD) is determined as the indicator for the biofunctional activity analysis of CTCs, compared with the existing morphological (EMT) classification on CTCs. The metabolic characterization of CTCs demonstrates that hypermetabolic GMCTCs are promising biomarkers for prostate cancer metastasis. 10.1186/s13046-018-0789-0
A Novel Peptide Probe for Identification of PLS3-Expressed Cancer Cells. Shi Fanghao,Ma Yan,Qian Yixia,Wang Yuehua,Wang Zihua,Zhao Minzhi,Hu Zhiyuan Analytical chemistry The T-plastin (PLS3) has a significant implication in epithelial-mesenchymal transition (EMT) and breast cancer prognosis. Using one-bead-one-compound library strategy, a novel peptide TP1 (KVKSDRVC) toward PLS3 was screened and exhibited the specificity for identifying PLS3-expressed cancer cells. Moreover, we found Fluorescein isothiocyanate-labeled TP1 (FITC-TP1) could act as a novel probe for EMT-induced cancer cells, preferentially in the leading edge. It also has satisfactory specificity for PLS3-expressed cancer cells spiked in the blood. FITC-TP1 was expected to become a diagnostic tool to identify PLS3-expressed circulating tumor cells and predict prognosis for patients with breast cancer in the future. 10.1021/acs.analchem.9b01061
Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells. Donato Cinzia,Kunz Leo,Castro-Giner Francesc,Paasinen-Sohns Aino,Strittmatter Karin,Szczerba Barbara Maria,Scherrer Ramona,Di Maggio Nunzia,Heusermann Wolf,Biehlmaier Oliver,Beisel Christian,Vetter Marcus,Rochlitz Christoph,Weber Walter Paul,Banfi Andrea,Schroeder Timm,Aceto Nicola Cell reports Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation. 10.1016/j.celrep.2020.108105
Detection of clustered circulating tumour cells in early breast cancer. British journal of cancer Circulating tumour cell (CTC) clusters have been proposed to be major players in the metastatic spread of breast cancer, particularly during advanced disease stages. Yet, it is unclear whether or not they manifest in early breast cancer, as their occurrence in patients with metastasis-free primary disease has not been thoroughly evaluated. In this study, exploiting nanostructured titanium oxide-coated slides for shear-free CTC identification, we detect clustered CTCs in the curative setting of multiple patients with early breast cancer prior to surgical treatment, highlighting their presence already at early disease stages. These results spotlight an important aspect of metastasis biology and the possibility to intervene with anti-cluster therapeutics already during the early manifestation of breast cancer. 10.1038/s41416-021-01327-8
The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper. Critical reviews in oncology/hematology BACKGROUND:The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS:In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV, those with < 5 CTCs as Stage IV Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS:For all patients, Stage IV patients had longer median overall survival than those with Stage IV (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV vs. 18.7 months Stage IV, p < 0.0001). Moreover, patients with Stage IV disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS:We confirm the identification of two subgroups of MBC, Stage IV and Stage IV, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials. 10.1016/j.critrevonc.2018.12.004
Circulating tumour cell-derived plastin3 is a novel marker for predicting long-term prognosis in patients with breast cancer. Ueo H,Sugimachi K,Gorges T M,Bartkowiak K,Yokobori T,Müller V,Shinden Y,Ueda M,Ueo H,Mori M,Kuwano H,Maehara Y,Ohno S,Pantel K,Mimori K British journal of cancer BACKGROUND:Identification of promising biomarkers that predict the prognosis of patients with breast cancer is needed. In this study, we hypothesised that the expression of the epithelial-mesenchymal transition-related biomarker plastin3 (PLS3) in peripheral blood could be a prognostic factor in breast cancer. METHODS:We examined PLS3 expression in breast cancer cell lines with epithelial and mesenchymal traits and in circulating tumour cells (CTCs) obtained from the peripheral blood of breast cancer patients. We investigated PLS3 expression in the peripheral blood of 594 patients with breast cancer to evaluate the clinical significance of PLS3 expression. RESULTS:Robust PLS3 expression was observed in different breast cancer cell lines (Hs578t, MCF-7, MDA-MB-468, and MDA-MB-231) as well as in a bone marrow derived cancer cell line (BC-M1). In both the training (n=298) and validation (n=296) sets, PLS3 expression was observed in CTCs of patients with breast cancer. PLS3-positive patients showed significantly poorer overall and disease-free survival than PLS3-negative patients (P=0.0001 and 0.003, respectively). Subset analysis revealed that this prognostic biomarker was relevant in patients with stage I-III cancer, particularly in patients with luminal-type and triple-negative-type tumours. CONCLUSIONS:These data demonstrated that PLS3 was expressed in CTCs undergoing the epithelial-mesenchymal transition in patients with breast cancer. Furthermore, PLS3 may be an excellent biomarker for identifying groups at risk of recurrence or with a poor prognosis. 10.1038/bjc.2015.132
Heterogeneous Manifestations of Epithelial-Mesenchymal Plasticity of Circulating Tumor Cells in Breast Cancer Patients. Tashireva Liubov A,Savelieva Olga E,Grigoryeva Evgeniya S,Nikitin Yuri V,Denisov Evgeny V,Vtorushin Sergey V,Zavyalova Marina V,Cherdyntseva Nadezhda V,Perelmuter Vladimir M International journal of molecular sciences To date, there is indisputable evidence of significant CTC heterogeneity in carcinomas, in particular breast cancer. The heterogeneity of CTCs is manifested in the key characteristics of tumor cells related to metastatic progression - stemness and epithelial-mesenchymal (EMT) plasticity. It is still not clear what markers can characterize the phenomenon of EMT plasticity in the range from epithelial to mesenchymal phenotypes. In this article we examine the manifestations of EMT plasticity in the CTCs in breast cancer. The prospective study included 39 patients with invasive carcinoma of no special type. CTC phenotypes were determined by flow cytometry before any type of treatment. EMT features of CTC were assessed using antibodies against CD45, CD326 (EpCam), CD325 (N-cadherin), CK7, Snail, and Vimentin. Circulating tumor cells in breast cancer are characterized by pronounced heterogeneity of EMT manifestations. The results of the study indicate that the majority of heterogeneous CTC phenotypes (22 out of 24 detectable) exhibit epithelial-mesenchymal plasticity. The variability of EMT manifestations does not prevent intravasation. Co-expression of EpCAM and CK7, regardless of the variant of co-expression of Snail, N-cadherin, and Vimentin, are associated with a low number of CTCs. Intrapersonal heterogeneity is manifested by the detection of several CTC phenotypes in each patient. Interpersonal heterogeneity is manifested by various combinations of CTC phenotypes in patients (from 1 to 17 phenotypes). 10.3390/ijms22052504
Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity. Koch Claudia,Kuske Andra,Joosse Simon A,Yigit Gökhan,Sflomos George,Thaler Sonja,Smit Daniel J,Werner Stefan,Borgmann Kerstin,Gärtner Sebastian,Mossahebi Mohammadi Parinaz,Battista Laura,Cayrefourcq Laure,Altmüller Janine,Salinas-Riester Gabriela,Raithatha Kaamini,Zibat Arne,Goy Yvonne,Ott Leonie,Bartkowiak Kai,Tan Tuan Zea,Zhou Qing,Speicher Michael R,Müller Volkmar,Gorges Tobias M,Jücker Manfred,Thiery Jean-Paul,Brisken Cathrin,Riethdorf Sabine,Alix-Panabières Catherine,Pantel Klaus EMBO molecular medicine Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC-derived breast cancer cell line, designated CTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER ) breast cancer, resistant to endocrine therapy. CTC-ITB-01 remained ER in culture, and copy number alteration (CNA) profiling showed high concordance between CTC-ITB-01 and CTCs originally present in the patient with cancer at the time point of blood draw. RNA-sequencing data indicate that CTC-ITB-01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductal PDX mouse model mirrored the clinical progression of ER breast cancer. Downstream ER signaling was constitutively active in CTC-ITB-01 independent of ligand availability, and the CDK4/6 inhibitor Palbociclib strongly inhibited CTC-ITB-01 growth. Thus, we established a functional model that opens a new avenue to study CTC biology. 10.15252/emmm.201911908
Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma. Sun Yun-Fan,Wu Liang,Liu Shi-Ping,Jiang Miao-Miao,Hu Bo,Zhou Kai-Qian,Guo Wei,Xu Yang,Zhong Yu,Zhou Xiao-Rui,Zhang Ze-Fan,Liu Geng,Liu Sheng,Shi Ying-Hong,Ji Yuan,Du Min,Li Nan-Nan,Li Gui-Bo,Zhao Zhi-Kun,Huang Xiao-Yun,Xu Li-Qin,Yu Qi-Chao,Peng David H,Qiu Shuang-Jian,Sun Hui-Chuan,Dean Michael,Wang Xiang-Dong,Chung Wen-Yuan,Dennison Ashley R,Zhou Jian,Hou Yong,Fan Jia,Yang Xin-Rong Nature communications Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC. 10.1038/s41467-021-24386-0
Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study. Chauhan Pradeep S,Chen Kevin,Babbra Ramandeep K,Feng Wenjia,Pejovic Nadja,Nallicheri Armaan,Harris Peter K,Dienstbach Katherine,Atkocius Andrew,Maguire Lenon,Qaium Faridi,Szymanski Jeffrey J,Baumann Brian C,Ding Li,Cao Dengfeng,Reimers Melissa A,Kim Eric H,Smith Zachary L,Arora Vivek K,Chaudhuri Aadel A PLoS medicine BACKGROUND:The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS:We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS:utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future. 10.1371/journal.pmed.1003732
Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA for precision medicine. Batth I S,Mitra A,Manier S,Ghobrial I M,Menter D,Kopetz S,Li S Annals of oncology : official journal of the European Society for Medical Oncology Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study. 10.1093/annonc/mdw619
Genomic characterization of metastatic breast cancers. Bertucci François,Ng Charlotte K Y,Patsouris Anne,Droin Nathalie,Piscuoglio Salvatore,Carbuccia Nadine,Soria Jean Charles,Dien Alicia Tran,Adnani Yahia,Kamal Maud,Garnier Séverine,Meurice Guillaume,Jimenez Marta,Dogan Semih,Verret Benjamin,Chaffanet Max,Bachelot Thomas,Campone Mario,Lefeuvre Claudia,Bonnefoi Herve,Dalenc Florence,Jacquet Alexandra,De Filippo Maria R,Babbar Naveen,Birnbaum Daniel,Filleron Thomas,Le Tourneau Christophe,André Fabrice Nature Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR) but did not have high levels of HER2 (HER2; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR/HER2 metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR/HER2 metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course. 10.1038/s41586-019-1056-z
Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Haber Daniel A,Velculescu Victor E Cancer discovery UNLABELLED:The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. SIGNIFICANCE:Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. 10.1158/2159-8290.CD-13-1014
Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA. van der Pol Ymke,Mouliere Florent Cancer cell Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going beyond DNA sequence information alone, by analyzing cfDNA epigenetic and immune signatures, boosts the potential of liquid biopsy for the early detection of cancer. 10.1016/j.ccell.2019.09.003
Precision medicine for metastatic breast cancer--limitations and solutions. Arnedos Monica,Vicier Cecile,Loi Sherene,Lefebvre Celine,Michiels Stefan,Bonnefoi Herve,Andre Fabrice Nature reviews. Clinical oncology The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials. 10.1038/nrclinonc.2015.123
Opportunities and Challenges for Pancreatic Circulating Tumor Cells. Nagrath Sunitha,Jack Rhonda M,Sahai Vaibhav,Simeone Diane M Gastroenterology Sensitive and reproducible platforms have been developed for detection, isolation, and enrichment of circulating tumor cells (CTCs)-rare cells that enter the blood from solid tumors, including those of the breast, prostate gland, lung, pancreas, and colon. These might be used as biomarkers in diagnosis or determination of prognosis. CTCs are no longer simply detected and quantified; they are now used in ex vivo studies of anticancer agents and early detection. We review what we have recently learned about CTCs from pancreatic tumors, describing advances in their isolation and analysis and challenges to their clinical utility. We summarize technologies used to isolate CTCs from blood samples of patients with pancreatic cancer, including immunoaffinity and label-free physical attribute-based capture. We explain methods of CTC analysis and how findings from these studies might be used to detect cancer at earlier stages, monitor disease progression, and determine prognosis. We review studies that have expanded CTCs for testing of anticancer agents and how these approaches might be used to personalize treatment. Advances in the detection, isolation, and analysis of CTCs have increased our understanding of the dissemination and progression of pancreatic cancer. However, standardization of methodologies and prospective studies are needed for this emerging technology to have a significant effect on clinical care. 10.1053/j.gastro.2016.05.052
Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Alix-Panabières Catherine,Pantel Klaus Cancer discovery UNLABELLED:"Liquid biopsy" focusing on the analysis of circulating tumor cells (CTC) and circulating cell-free tumor DNA (ctDNA) in the blood of patients with cancer has received enormous attention because of its obvious clinical implications for personalized medicine. Analyses of CTCs and ctDNA have paved new diagnostic avenues and are, to date, the cornerstones of liquid biopsy diagnostics. The present review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms. SIGNIFICANCE:The application of CTCs and ctDNA for the early detection of cancer is of high public interest, but it faces serious challenges regarding specificity and sensitivity of the current assays. Prediction of prognosis in patients with curable disease can already be achieved in several tumor entities, particularly in breast cancer. Monitoring the success or failure of systemic therapies (i.e., chemotherapy, hormonal therapy, or other targeted therapies) by sequential measurements of CTCs or ctDNA is also feasible. Interventional studies on treatment stratification based on the analysis of CTCs and ctDNA are needed to implement liquid biopsy into personalized medicine. Cancer Discov; 6(5); 479-91. ©2016 AACR. 10.1158/2159-8290.CD-15-1483
Clinical indications for, and the future of, circulating tumor cells. Moon Dominic H,Lindsay Daniel P,Hong Seungpyo,Wang Andrew Z Advanced drug delivery reviews Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered circulation with potential to initiate a site of metastasis. Currently, CTC detection using CellSearch is cleared by the Food and Drug Administration for monitoring metastatic breast, prostate, and colorectal cancers as a prognostic biomarker for progression-free and overall survival. Accumulating evidence suggests CTCs have similar prognostic value in other metastatic and non-metastatic settings. Current research efforts are focused on extending the utility of CTCs beyond a prognostic biomarker to help guide clinical decision-making. These include using CTCs as a screening tool for diagnosis, liquid biopsy for molecular profiling, predictive biomarker to specific therapies, and monitoring tool to assess response and guide changes to treatment. CTCs have unique advantages vs circulating tumor DNA in this endeavor. Indications for CTCs in daily practice will expand as isolation techniques improve and clinical studies validating their utility continue to grow. 10.1016/j.addr.2018.04.002
Clinical applications of the CellSearch platform in cancer patients. Riethdorf Sabine,O'Flaherty Linda,Hille Claudia,Pantel Klaus Advanced drug delivery reviews The CellSearch® system (CS) enables standardized enrichment and enumeration of circulating tumor cells (CTCs) that are repeatedly assessable via non-invasive "liquid biopsy". While the association of CTCs with poor clinical outcome for cancer patients has clearly been demonstrated in numerous clinical studies, utilizing CTCs for the identification of therapeutic targets, stratification of patients for targeted therapies and uncovering mechanisms of resistance is still under investigation. Here, we comprehensively review the current benefits and drawbacks of clinical CTC analyses for patients with metastatic and non-metastatic tumors. Furthermore, the review focuses on approaches beyond CTC enumeration that aim to uncover therapeutically relevant antigens, genomic aberrations, transcriptional profiles and epigenetic alterations of CTCs at a single cell level. This characterization of CTCs may shed light on the heterogeneity and genomic landscapes of malignant tumors, an understanding of which is highly important for the development of new therapeutic strategies. 10.1016/j.addr.2018.01.011
Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Keller Laura,Pantel Klaus Nature reviews. Cancer Single-cell technologies have contributed to unravelling tumour heterogeneity, now considered a hallmark of cancer and one of the main causes of tumour resistance to cancer therapies. Liquid biopsy (LB), defined as the detection and analysis of cells or cell products released by tumours into the blood, offers an appealing minimally invasive approach that allows the characterization and monitoring of tumour heterogeneity in individual patients. Here, we will review and discuss how circulating tumour cell (CTC) analysis at single-cell resolution provides unique insights into tumour heterogeneity that are not revealed by analysis of circulating tumour DNA (ctDNA) derived from LBs. The molecular analysis of CTCs provides complementary information to that of genomic aberrations determined using ctDNA to fully describe many different cellular components (for example, DNA, RNA, proteins and metabolites) that can influence tumour heterogeneity. 10.1038/s41568-019-0180-2