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    XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer. Zhao Yahui,Zhang Weina,Huo Miaomiao,Wang Peng,Liu Xianghe,Wang Yu,Li Yinuo,Zhou Zhixiang,Xu Ningzhi,Zhu Hongxia Signal transduction and targeted therapy Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206 TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking "don't eat me" recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy. 10.1038/s41392-021-00761-7
    Heterogeneity of human prostate carcinoma-associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment. Vickman Renee E,Broman Meaghan M,Lanman Nadia A,Franco Omar E,Sudyanti Putu Ayu G,Ni Yang,Ji Yuan,Helfand Brian T,Petkewicz Jacqueline,Paterakos Michael C,Crawford Susan E,Ratliff Timothy L,Hayward Simon W The Prostate BACKGROUND:Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized. METHODS:Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment. RESULTS:Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity. CONCLUSIONS:CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued. 10.1002/pros.23929
    Identify potential prognostic indicators and tumor-infiltrating immune cells in pancreatic adenocarcinoma. Shi Ting,Gao Ge Bioscience reports BACKGROUND:Pancreatic adenocarcinoma (PAAD) is a kind of highly malignant tumor and lacks early diagnosis method and effective treatment. Tumor microenvironment (TME) is of great importance for the occurrence and development of PAAD. Thus, a comprehensive overview of genes and tumor-infiltrating immune cells (TICs) related to TME dynamic changes conduce to develop novel therapeutic targets and prognostic indicators. METHODS:We used MAlignant Tumors using Expression data (ESTIMATE) algorithm to analyze the transcriptome RNA-seq data of 182 PAAD cases on The Cancer Genome Atlas (TCGA) platform. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) network, COX regression analysis and gene set enrichment analysis (GSEA) were carried out to get the hub genes related to the prognosis of PAAD patients. These core genes were validated in GEPIA. CXCL10 expression as a poor prognostic indicator was validated in GEO database. Finally, CIBERSORT algorithm was applied to understand the status of TICs. RESULTS:A total of 715 up-regulated differential expression genes (DEGs) and 57 down-regulated DEGs were found simultaneously in stromal and immune groups. These DEGs were mainly enriched in immune recognition, activation and response processes. CD4, CXCL12, CXCL10, CCL5 and CXCL9 were the top five core genes. Then, the validation of these genes showed that CD4, CXCL10, CXCL5, CXCL9 were up-regulated in PAAD. Among the core genes, CXCL10 had a negative correlation with the survival time of PAAD patients. CD8+ T cells, CD4+ T cells memory activated, macrophages M1 had positive correlation of CXCL10 expression, whereas regulatory T cells (Tregs), macrophages M0 and B cells memory had negative correlation. CONCLUSION:We generated a series of genes related to TME with prognostic implications and TICs in PAAD, which have the potential to be novel immunotherapy targets and prognostic markers. The data showed that CXCL10 was favorable as a poor prognostic indicator in PAAD patients. 10.1042/BSR20212523
    Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer. Hornburg Milena,Desbois Mélanie,Lu Shan,Guan Yinghui,Lo Amy A,Kaufman Susan,Elrod Ashley,Lotstein Alina,DesRochers Teresa M,Munoz-Rodriguez Jose L,Wang Xingwei,Giltnane Jennifer,Mayba Oleg,Turley Shannon J,Bourgon Richard,Daemen Anneleen,Wang Yulei Cancer cell Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies. 10.1016/j.ccell.2021.04.004
    Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer. Li Xuechun,Sun Zhao,Peng Gongxin,Xiao Yi,Guo Junchao,Wu Bin,Li Xiaoyi,Zhou Weixun,Li Jiarui,Li Zhe,Bai Chunmei,Zhao Lin,Han Qin,Zhao Robert Chunhua,Wang Xiaoyue Theranostics The protumor activities of cancer-associated fibroblasts (CAFs) suggest that they are potential therapeutic targets for the treatment of cancer. The mechanism of CAF heterogeneity in gastric cancer (GC) remains unclear and has slowed translational advances in targeting CAFs. Therefore, a comprehensive understanding of the classification, function, activation stage, and spatial distribution of the CAF subsets in GC is urgently needed. In this study, the characteristics of the CAF subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by the CAF subsets were analyzed by performing single-cell RNA sequencing of eight pairs of GC and adjacent mucosal (AM) samples. The spatial distribution of the CAF subsets in different Lauren subtypes of GC, as well as the neighborhood relations between these CAF subsets and the protumor immune cell subsets were evaluated by performing multistaining registration. Tumor epithelial cells exhibited significant intratumor and intertumor variabilities, while CAFs mainly exhibited intratumor variability. Moreover, we identified four CAF subsets with different properties in GC. These four CAF subsets shared similar properties with their resident fibroblast counterparts in the adjacent mucosa but also exhibited enhanced protumor activities. Additionally, two CAF subsets, inflammatory CAFs (iCAFs) and extracellular matrix CAFs (eCAFs), communicated with adjacent immune cell subsets in the GC TME. iCAFs interacted with T cells by secreting interleukin (IL)-6 and C-X-C motif chemokine ligand 12 (CXCL12), while eCAFs correlated with M2 macrophages via the expression of periostin (POSTN). eCAFs, which function as a pro-invasive CAF subset, decreased the overall survival time of patients with GC. iCAFs and eCAFs not only exhibited enhanced pro-invasive activities but also mobilized the surrounding immune cells to construct a tumor-favorable microenvironment. Therefore, inhibiting their activation restrains the GC 'seed' and simultaneously improves the 'GC' soil, suggesting that it represents a promising therapeutic strategy for the treatment of GC. 10.7150/thno.60540