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ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [RIP-seq]

ABSTRACT: The role of N6-methyladenosine (m6A) in pancreatic ductal adenocarcinoma (PDAC) progression has garnered significant attention, yet its specific function within cancer-associated fibroblasts (CAFs)—key players in the tumor microenvironment—remains poorly understood. Here, using both primary and immortalized CAFs that we established from patient-derived samples, we identified m6A demethylase AlkB homolog 5 (ALKBH5) as a critical regulator of CAF-driven PDAC metastasis. We show that CAF activation induces a global reduction in m6A levels, with ALKBH5 emerging as a core modulator of the m6A epitranscriptome. Mechanistically, ALKBH5 enhances the m6A-dependent translational efficiency of heat shock factor 1 (HSF1), which in turn activates leukemia inhibitory factor (LIF) transcription by binding to its enhancer elements. Paracrine LIF signaling promotes epithelial–mesenchymal transition in pancreatic cancer cells, thereby facilitating tumor metastasis to the liver and lungs. Clinically, enrichment of ALKBH5+HSF1+ CAFs is strongly associated with poor prognosis and is predominantly observed in primary PDAC with metastasis. Together, this work demonstrates a CAF–intrinsic ALKBH5–HSF1–LIF axis as a critical driver of PDAC metastasis, suggesting a promising therapeutic strategy targeting the tumor stroma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304433 | GEO | 2026/06/26

REPOSITORIES: GEO

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ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [MeRIP-seq]

Project description:The role of N6-methyladenosine (m6A) in pancreatic ductal adenocarcinoma (PDAC) progression has garnered significant attention, yet its specific function within cancer-associated fibroblasts (CAFs)—key players in the tumor microenvironment—remains poorly understood. Here, using both primary and immortalized CAFs that we established from patient-derived samples, we identified m6A demethylase AlkB homolog 5 (ALKBH5) as a critical regulator of CAF-driven PDAC metastasis. We show that CAF activation induces a global reduction in m6A levels, with ALKBH5 emerging as a core modulator of the m6A epitranscriptome. Mechanistically, ALKBH5 enhances the m6A-dependent translational efficiency of heat shock factor 1 (HSF1), which in turn activates leukemia inhibitory factor (LIF) transcription by binding to its enhancer elements. Paracrine LIF signaling promotes epithelial–mesenchymal transition in pancreatic cancer cells, thereby facilitating tumor metastasis to the liver and lungs. Clinically, enrichment of ALKBH5+HSF1+ CAFs is strongly associated with poor prognosis and is predominantly observed in primary PDAC with metastasis. Together, this work demonstrates a CAF–intrinsic ALKBH5–HSF1–LIF axis as a critical driver of PDAC metastasis, suggesting a promising therapeutic strategy targeting the tumor stroma.

2026-06-26 | GSE304436 | GEO

ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [ATAC-seq]

Project description:Cancer-associated fibroblasts (CAFs) are principal determinants of pancreatic ductal adenocarcinoma (PDAC) progression, yet the epitranscriptomic mechanisms governing tumor–stroma crosstalk remain poorly understood. Here, we identify N6-methyladenosine (m6A) remodeling as a hallmark of CAF activation and define a critical role for the m6A demethylase AlkB homolog 5 (ALKBH5) in PDAC metastasis. Activated CAFs exhibit a global reduction in m6A abundance, with ALKBH5 emerging as a key regulator of the CAF epitranscriptome. Functionally, CAF-derived ALKBH5 enhances pancreatic cancer cell migration and invasion in vitro and promotes epithelial–mesenchymal transition–associated gene expression in tumor cells in an m6A-dependent manner. In vivo, orthotopic co-implantation models and host genetic ablation models demonstrate that ALKBH5 plays a critical role in metastatic dissemination, with minimal impact on primary tumor growth. Mechanistically, ALKBH5 enhances the m6A-dependent translation of heat shock factor 1 (HSF1) in CAFs, at least in part by relieving insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-associated translational constraints. Elevated HSF1 subsequently activates leukemia inhibitory factor (LIF) transcription through distal enhancer elements, establishing an ALKBH5–HSF1–LIF signaling axis that mediates pro-metastatic CAF–tumor cell communication. Clinically, enrichment of ALKBH5⁺/HSF1⁺ CAFs independently predicts poor prognosis and is preferentially observed in metastatic PDAC. Collectively, these findings uncover a CAF-intrinsic epitranscriptomic program that drives PDAC metastasis and highlight stromal m6A regulation as a potential therapeutic vulnerability.

2026-06-26 | GSE316466 | GEO

ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [CUT&Tag]

2026-06-26 | GSE304431 | GEO

Expression data from gemcitabine treated pancreatic CAFs

Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naÃ¯ve CAFs (N-CAFs) and R-CAFs were compared by array analysis. Immortalized human pancreatic CAFs were grown for 30 days in either control media or media containing 100nM gemcitabine. RNA was then isolated and hybidized on U133 Plus 2.0 Affymetrix arrays.

2016-03-09 | E-GEOD-78982 | biostudies-arrayexpress

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.

2022-10-10 | GSE200616 | GEO

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

2022-10-10 | GSE200615 | GEO

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

2022-10-10 | GSE200613 | GEO

Single-Cell Analysis of Human Pancreatic Ductal Adenocarcinoma

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

RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors (IOA-289 and PF-8380) against DMSO treated controls

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

Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma impair CD8+ T cell activation and limit responsiveness to immunotherapy in mice

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.

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