Pancreatic stellate cell-secreted FGF9 activates and stabilizes c-Myc to drive pancreatic ductal adenocarcinoma cell proliferation

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that is driven by activated pancreatic stellate cells (PSCs). However, how PSC-derived paracrine signals promote PDAC cell proliferation remains incompletely understood. Transcriptome sequencing was used to compare activated primary human PSCs with matched cultures treated with all-trans retinoic acid. Fibroblast growth factor 9 (FGF9) function was evaluated in PDAC cells using PSC-conditioned medium, recombinant FGF9, and a neutralizing antibody, as well as in an orthotopic mouse model. Receptor knockdown and rescue, protein stability and ubiquitination assays, pathway inhibition, and chromatin immunoprecipitation were used to investigate downstream mechanisms. Human PDAC tissues were examined by immunostaining. FGF9 expression and secretion increased in activated PSCs, and stromal expression was confirmed in human PDAC tissues. PSC-derived FGF9 promoted PDAC cell proliferation and G1/S transition, whereas FGF9 depletion in PSCs reduced orthotopic tumour growth. Fibroblast growth factor receptor 3 (FGFR3) mediated the proliferative response to FGF9 in cultured PDAC cells. FGF9–FGFR3 signalling stabilized c-Myc by reducing its ubiquitin–proteasome-mediated degradation, with ERK and Akt contributing to c-Myc accumulation. Further analyses identified a c-Myc-regulated PINK1-AS/PINK1 module as a candidate downstream link to cell-cycle regulation. PSC-derived FGF9 promotes PDAC cell proliferation and tumour growth. FGF9–FGFR3 signalling links stromal cues to c-Myc protein stabilization, highlighting this axis as a potential therapeutic target in PDAC.