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Fibroblast-Derived Thrombospondin 2 Shapes the Immune-Exclusionary Environment at Invasive Fronts in Colorectal Cancer [RNA-seq_Human_CRC]

ABSTRACT: Fibrotic colorectal cancers (CRC) are characterized by immune exclusion driven by activated stroma, particularly by cancer-associated fibroblasts (CAFs). We identified that the matricellular protein thrombospondin-2 (THBS2) is highly expressed in the stroma of fibrotic CRCs. We performed orthotopic implantation of CMS4-like mouse tumor organoid (MTO) into WT and Thbs2 KO mice. Tumors developed in Thbs2 KO mice were considerably smaller and exhibited increased CD8 T cell infiltration and higher numbers of apoptotic tumor cells compared with WT mice. This study aims to elucidate the interaction between fibrotic CRCs and CAFs by comparing the phenotypic characteristics of bulk tumor tissues and their corresponding CAFs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285503 | GEO | 2025/10/28

REPOSITORIES: GEO

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Fibroblast-Derived Thrombospondin 2 Shapes the Immune-Exclusionary Environment at Invasive Fronts in Colorectal Cancer [scRNA-seq]

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Fibroblast-Derived Thrombospondin 2 Shapes the Immune-Exclusionary Environment at Invasive Fronts in Colorectal Cancer [Visium

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Project description:Gastric cancer is the 3rd most lethal cancer worldwide, and the genomic status of its cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), and in particular cancer-associated fibroblasts (CAFs). However, very little is known about the role of CAFs in gastric cancer. To address this, we map the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. We find a stromal gene signature associated with poor disease outcome. This signature is regulated by the transcription factor Heat Shock Factor 1 (HSF1), that activates CAF-derived extracellular vesicles (EVs) that transfer components including Inhibin Subunit Beta A (INHBA) and Thrombospondin 2 (THBS2), to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma, and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.

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Tumor-reactive T cells in HNSCC patients are directed against cancer-associated fibroblasts

Project description:Endogenous T-cell (TC) responses against tumors determine patient prognosis and are the basis for successful immune checkpoint-blocking cancer immunotherapy. Yet, cell subsets and antigens they target in the tumor microenvironment remain largely unknown. In contrast to tumor cells, which are a clonally diverse and unstable cell population, non-malignant cells of the tumor stroma, particularly cancer-associated fibroblasts (CAFs) represent a large subset of genetically stable cells which nonetheless essentially contribute to tumor progression in many cancers. Here, we studied in a cohort of HNSCC patients to what degree tumor-reactive TCs may target CAFs and which CAF-associated antigens are recognized. Using autologous TCs, tumor cell, and CAF cultures from HNSCC patients, we show that tumor-reactive type 1 TC responses against CAFs commonly occur in HNSCC patients to a similar extent as TC responses against the tumor cells themselves. Due to simultaneous MHC-I and -II expression, CAFs were directly recognized by CD8+ cytotoxic and CD4+ helper TCs. Then, we performed automated 2D proteome fractionation of CAF lysates together with mass spectrometry-based proteome identification, differential transcriptome analyses of CAFs and laser-capture-microdissected tumor stroma and TC function assays. We identified several common antigens including TXNDC17, NANS, DNAJB11, and THBS2 being differentially expressed on CAFs and recognized by tumor-reactive TC repertoires of multiple patients. Taken together, CAFs are a major target cell type of tumor-reactive TC responses in HNSCC patients. Due to their MHC-II expression, differential expression of common CAF-selective immunogenic antigens and their essential role during tumor progression, they represent promising targets for anti-cancer immunotherapies.

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Carcinoma-associated fibroblasts stimulate cancer cell invasion by mechanically remodeling the basement membrane

Project description:The first step in metastasis is dissemination of tumor cells into the surrounding tissue, or stroma. In carcinomas, cancers of epithelial origin, tumor cells must first breach the basement membrane (BM), a network that encapsulates the tumor. As tumor progresses, other cell types that reside in the stroma, such as carcinoma-associated fibroblasts (CAFs) accumulate around the tumor. Whether CAFs can help cancer cells to breach the BM remains an open question. Here we show that CAFs promote cancer cell invasion by physically remodeling the BM. Using a novel 3D in vitro model we observed that primary CAFs isolated from colon cancer patients stimulate cancer cell invasion through a native mesenteric BM. This stimulated invasion is the result of the physical presence of CAFs rather than an increased invasive potential of cancer cells. In the presence of CAFs, cancer cells can invade the BM in a matrix metalloproteinase-independent manner. Using live imaging, we found that CAFs actively pull and stretch the BM, leading to the formation of gaps through which cancer cells can migrate. Notably, CAF-mediated gap-widening is independent of proteolysis but relies on actomyosin contractility. We propose that CAFs exert mechanical forces that alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion.

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Tumor-stroma IL-1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemo-resistance and Poor Prognosis in Pancreatic Cancer

Project description:Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemoresistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo. Moreover, high IL-1b expression by immunohistochemistry in PDAC stroma is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC.

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