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

Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma with context-dependent tumor-restraining and tumor-promoting functions, highlighting the need to selectively reprogram stromal states. Although intratumoral coagulation activity is frequently observed, its role in driving these states remains unclear. Here, we identify extravascular coagulation as a tumor-amplified regulatory module that stabilizes pro-fibrotic stromal states via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To establish clinical relevance and enable mechanistic interrogation, we combined human tumor bioinformatics with a cross-scale experimental workflow integrating microphysiological tumor-stroma (MPTS) models and in vivo systems to define and test this regulatory axis. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression across tumors, with elevated expression associated with fibrotic transcriptional programs and reduced survival. Consistently, thrombin induced coordinated pro-fibrotic programs in tumor cells and cancer-associated fibroblasts (CAFs), which were recapitulated in microphysiological models where tumor-intrinsic PAR1 was required for amplification of extracellular matrix deposition and CAF activation. Mechanistically, PAR1 signaling amplified tumor-stroma communication, in part through induction of TGF-{beta}1-dependent pathways, establishing a reinforcing feedback loop that stabilizes fibrotic remodeling. Pharmacologic inhibition of PAR1 suppressed pro-fibrotic CAF states, reprogrammed stromal states and attenuated tumor progression across microphysiological and in vivo models. These findings establish extravascular coagulation as a systems-level regulator of stromal state architecture in PDAC and define a cross-scale framework for targeting tumor-stroma regulatory circuits.