Senescent carcinoma associated fibroblasts up-regulate interleukin 8 to enhance pancreatic cancer progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81368 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA321383
REPOSITORIES: GEO
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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:Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
2024-06-06 | GSE235244 | GEO
Project description:Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
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Project description:Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
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Project description:Senescent cells secrete many molecules, which contribute to the prevention of cancer progression. We induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. The first two are considered inducers of acute senescence while extensive proliferation triggers replicative senescence also named chronic senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC conditioned media and evaluated proliferation, DNA damage, apoptosis and senescence.
2018-10-25 | PXD003018 | Pride
Project description:CSCs may be regulated by extrinsic signals provided by specialized microenvironments, or niches, which sustain CSC expansion. We investigated the role of cancer associated fibroblasts (CAFs) in the regulation of CSCs using a genetically engineered mouse model of basal-like breast cancer driven by combined activation of Wnt/β-catenin and HGF/Met signaling (Wnt-Met mice). We found that CAFs secrete soluble factors that promote the expansion of the population of self-renewing cells that generate mammospheres and enhance the capacity of CSCs to form invasive 3D structures. Using transcriptional profiling, we identified a network of paracrine interactions between CAFs and CSCs that regulate reciprocal functions.
2018-04-23 | GSE68241 | GEO
Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.
2022-09-20 | GSE190998 | GEO
Project description:The p53 protein is a cell-autonomous tumor suppressor that restricts malignant transformation by triggering cell cycle exit or apoptosis. p53 also promotes cellular senescence, a program that triggers a stable cell cycle arrest and can modify the tissue microenvironment through its effect on cell membrane and secretory proteins. Here we show that specific ablation of p53 in hepatic stellate cells, which undergo a process of proliferation and senescence in the fibrogenic response to liver damage, enhances liver cirrhosis, reduces survival and increases the malignant transformation of adjacent epithelial cells into hepatocellular carcinoma. This p53-dependent senescence program involves the release of secreted proteins which skew macrophages into a tumor-inhibiting M1-state that can eliminate senescent stellate cells. In contrast, p53-deficient stellate cells secrete factors that promote M2 polarization, which is pro-tumorigenic. Our study reveals that p53 can exert a non-cell-autonomous tumor suppressor response and suggests that this occurs, in part, by its ability to influence macrophage polarization. We used microarrays to detail the global programme of gene expression underlying p53-dependent senescent and identified distinct classes of up-regulated or down-regulated genes during this process. Proliferating and senescent stellate cell pellets were collected RNA extraction and hybridization on Affymetrix microarrays.
2013-04-05 | E-GEOD-39469 | biostudies-arrayexpress
Project description:Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib.
2024-06-24 | GSE253523 | GEO
Project description:The presence of senescent cells in the aging/degenerating human disc is now well-recognized. Senescent cells are viable, cannot divide, remain metabolically active and accumulate within the disc over time. Molecular analysis of senescent cells in tissue, however, offers a special challenge since there are no cell surface markers for senescence which would let one use fluorescence-activated cell sorting as a method for separating out senescent cells. Here we use a novel experimental design using laser capture microdissection to selectively separately harvest senescent and non-senescent annulus cells in paraffin-embedded tissue, and then compare their gene expression with microarray analysis. An initial in vitro study using cultured human annulus cells was first performed to test whether there was any difference in identification of senescent cells using the accepted histochemical methodology vs. the immunofluoresent identification of cells positive for senescence-associated-ß-galactosidase in control cells and cells induced into stress-induced premature senescence via hydrogen peroxide exposure. No statistically significant difference was found between the 2 methods. Laser capture microdissection was used to separately harvest senescent and non-senescent cells from 11 human annulus specimens, and microarray analysis was used to determine gene expression levels. Genes with established relationships to senescence were found to be significantly upregulated in senescent cells vs. non-senescent cells. Additional genes related to cytokines, cell proliferation, and other cell processes were also identified. Disc Tissue samples were obtained from surgical disc procedures performed on patients with herniated discs and degenerative disc disease. Tissue was fixed and paraffin embedded. Standard laser capture microdissection (LCM) techniques were used to collect senescent cells. Remaining non-senescent cells were scraped from the histology slide. Total RNA was isolated and analyzed via mircoarray. Gene expression from senescent cells was compared to non-senescent cells. Eight histological samples were used to obtain both senescent and non-senescent cells. From an additional 3 samples, only senescent cells were harvested.
2009-07-15 | E-GEOD-17077 | biostudies-arrayexpress