CAF-derived PTGDS drives pancreatic cancer neuroendocrine differentiation and chemoresistance via PAQR9-MAPK.

The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences pancreatic ductal adenocarcinoma (PDAC) progression. Neuroendocrine differentiation (NED) is associated with aggressive tumor behavior and therapy resistance in multiple malignancies, yet its regulation within the PDAC environment is poorly characterized. Through integrated analysis of clinical specimens and transcriptomic datasets, we identified significant enrichment of NED markers correlating with poor patient outcomes. Single-cell RNA sequencing further identified Glycoprotein prostaglandin D2 synthase (PTGDS) as a CAF-derived factor potentially driving NED. Functional studies demonstrated that PTGDS secreted by CAFs robustly induced NED while enhancing proliferation, invasion, migration, and gemcitabine resistance in pancreatic cancer cells. Mechanistically, we established that PTGDS activates MAPK signaling through its membrane receptor PAQR9, and the pharmacological inhibition of MAPK signaling or knockdown of PAQR9 effectively reversed PTGDS-induced malignant phenotypes. These findings reveal a novel CAFs/PTGDS-PAQR9-MAPK signaling axis that promotes NED and drives PDAC progression, offering new therapeutic opportunities to overcome stromal-mediated chemoresistance.