Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221761 | GEO | 2023/02/18
REPOSITORIES: GEO
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Project description:<p>Cancer-associated fibroblasts (CAFs) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we employ single-cell RNA-sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human PDAC tumors. Six human PDAC tumor specimens from six patients were collected, and processed for single-cell RNA-sequencing analysis. Adjacent-normal pancreas tissue was also collected from two of the patients. Tumor samples were digested, and fluorescence-activated cell sorting was used to isolate viable cells. For one tumor sample, viable, CD45-negative, CD31-negative, and EpCAM-negative cells were also isolated to enrich for CAFs. The 10X Chromium platform was then used to isolate single cells for RNA-sequencing analysis. This work has demonstrated the differences in immune cell populations between adjacent-normal and tumor tissues, and identified subpopulations of epithelial cells and CAFs present in PDAC tumors. This high-throughput analysis is a resource to better understand the cell populations present in PDAC, and may ultimately aid in the development of more effective therapies for this deadly malignancy.</p>
| phs001840 | dbGaP
Project description:Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.
2024-06-21 | GSE255978 | GEO
Project description:Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.
2024-03-15 | GSE254384 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and -suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis in KPC mice indicated that OGN is derived from a subgroup of inflammatory CAFs. OGN-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts.
2022-08-23 | GSE197908 | GEO
Project description:Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.
2024-10-06 | E-MTAB-14494 | biostudies-arrayexpress
Project description:Tumor stroma of pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant and heterogeneous cancer-associated fibroblasts (CAFs) that are critically involved in chemoresistance. However, the underlying mechanism of CAFs in chemoresistance is unclear. Here, we show that CAFR, a CAFs subset derived from oxaliplatin-resistant PDAC patients, produces more IL8 than CAFS isolated form oxaliplatin-sensitive PDAC patients. CAFR derived IL8 promotes PDAC oxaliplatin chemoresistance. Base on long non-coding RNA (lncRNA) profiling in tumor cells incubated with CAF, we identify that UPK1A-AS, which is directly induced by IL8/NF-kappa B signaling, functions as a pro-chemoresistant lncRNA and is critical for active IL8-induced oxaliplatin resistance. Impressively, blocking UPK1A-AS1 activation increases sensitivity of tumor cell response to oxaliplatin chemotherapy in vivo. Mechanically, UPK1A-AS1 strengths the interaction of Ku70 and Ku80 to enhance double-strand DNA break (DSB) repair, thereby coordinating the NHEJ pathway. Clinically, UPK1A-AS1 expression is positively correlated with IL8 expression, poor chemotherapeutic response and shorter PFS of PDAC patients. Collectively, our study discovers a lncRNA-mediated mechanism for CAF derived IL8 paracrine-dependent oxaliplatin resistance and highlights UPK1A-AS1 as potential therapeutic targets.
2021-09-16 | GSE183779 | GEO
Project description:Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
2024-06-24 | PXD053144 | Pride
Project description:Cancer-associated fibroblasts (CAFs) are among the most abundant cell types in desmoplastic tumors. However, CAFs are not yet a treatment target in mainstream cancer therapy likely because CAF heterogeneity and their roles in solid tumors remain incompletely understood. Here, we explored CAF heterogeneity via single-cell gene expression and chromatin accessibility in conjunction with spatial transcriptomics. We found that CAF heterogeneity is recapitulated across solid tumor types and species, and CAF subpopulations fall into two functional categories: mechano-responsive and immuno-modulatory. These categories are spatially-distinct and governed by specific changes in chromatin accessibility. Selective disruption of underlying mechanical force or immune signaling results in predictable shifts in subpopulation distributions and impacts tumor growth. Collectively, this research elucidates the spatial dynamics of CAF biology, delineates CAF subpopulation functions, identifies CAF-specific treatment factors, and provides a multimodal -omics framework for understanding the tumor stromal niche.
2023-02-01 | GSE179705 | GEO
Project description:Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for PDAC survival upon glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in an NUFIP1-depenent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.
2021-10-19 | GSE185750 | GEO
Project description:We used a dual recombinase mouse model to delete Hif2a in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2a expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results. CAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions. Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
2022-07-20 | GSE193416 | GEO