Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma that can restrain or promote tumor, highlighting the need to selectively reprogram stromal states. This study identifies extravascular coagulation as an upstream regulator of fibrotic stroma via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To interrogate this axis mechanistically, we combined human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models and in vivo systems. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression correlates with pro-fibrotic programs and reduced survival. Across MPTS and in vivo systems, thrombin-PAR1 signaling increased extracellular matrix deposition, activated cancer-associated fibroblasts (CAFs), and strengthened tumor-stroma communication, partly through TGF-β1-dependent pathways, establishing a self-reinforcing loop. PAR1 inhibition disrupted this loop, selectively suppressed the myofibroblastic CAF transcriptional program while reducing other CAF subtypes and attenuating tumor progression. These findings establish the coagulation-PAR1 axis as an upstream organizer of PDAC stroma and a promising target for selectively reprogramming tumor-promoting stroma.