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BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (KPC)

ABSTRACT: Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. Using cancer organoids, co-cultures and in-vivo models we show that loss of BRCA function in cancer cells leads to a transcriptional shift of pancreatic stellate cells from myofibroblastic into immune-regulatory CLU+ CAFs. This process is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research.

ORGANISM(S): Mus musculus

PROVIDER: GSE200615 | GEO | 2022/10/10

REPOSITORIES: GEO

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BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (PSC)

Project description:Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. Using cancer organoids, co-cultures and in-vivo models we show that loss of BRCA function in cancer cells leads to a transcriptional shift of pancreatic stellate cells from myofibroblastic into immune-regulatory CLU+ CAFs. This process is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research.

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BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling

Project description:BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling

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Genes activated by 5-aza-dC (DAC) in pancreatic cancer (KPC-Brca1) epithelial cells

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2013-01-01 | E-GEOD-42365 | biostudies-arrayexpress

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (PSC)

Project description:BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (PSC)

| PRJNA825537 | ENA

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (CAF)

Project description:BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (CAF)

| PRJNA825539 | ENA

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (KPC)

Project description:BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (KPC)

| PRJNA825538 | ENA

RNA sequencing of sorted cells from mouse PDAC

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplatic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts (NPFs) to identify genes potentially implicated in their pro-tumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the acute-phase Serum Amyloid A (SAA) apolipoprotein family, is a key mediator of the pro-tumorigenic activity of PDGFRα+ CAFs. Whereas Saa3 competent CAFs stimulate the growth of PDAC tumor cells in an orthotopic model, Saa3 null CAFs inhibit tumor growth. Saa3 also plays a role in the cross-talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3 null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC tumor development in mice. The pro-tumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases. Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the orthologue of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.

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