{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE316nnn/GSE316466/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316466"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"ALKBH5 in Cancer-associated Fibroblasts Facilitates Pancreatic Cancer Metastasis via HSF1–LIF Axis [ATAC-seq]","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.","dates":{"publication":"2026/06/26"},"accession":"GSE316466","cross_references":{"GSM":["GSM9453606","GSM9453607","GSM9453604","GSM9453605"],"GPL":["24676"],"GSE":["316466"],"taxon":["Homo sapiens"]}}