Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma
- 1University of Illinois Urbana-Champaign
Abstract
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. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained 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 interrogate this axis mechanistically, we integrated human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models that reconstruct tumor-stroma interactions under controlled coagulation exposure, followed by cross-scale validation in vivo. 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 MPTS 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 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.
Related
- Intrinsic-like blood coagulation activity in fish: Involvement of hepatocyte growth factor activator and interspecific diversity
- Intrinsic timescale develops hierarchically from sensorimotor to association cortex in youth and stabilizes in adulthood
- ESCO1 stabilizes NUFIP2 through acetylation–ubiquitination crosstalk to promote pancreatic cancer progression
- Borderline resectable pancreatic ductal adenocarcinoma: a narrative review
- Combined halp and GRIm scores for risk stratification in metastatic pancreatic ductal adenocarcinoma
BibTeX
@misc{choi2026extravascular,
title = {{Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma}},
author = {S. R. Choi and N. O. Munoz and H.-r. Moon and S. M. Utturkar and D. Do and Y. Chang and X. Bao and A. D. Cox and T. L. Ratliff and C. Conrad and M. Fishel and M. Flick and N. A. Lanman and B. D. Elzey and B. Han},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.25.734662},
url = {https://www.biorxiv.org/content/10.64898/2026.06.25.734662v4},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma
AU - S. R. Choi
AU - N. O. Munoz
AU - H.-r. Moon
AU - S. M. Utturkar
AU - D. Do
AU - Y. Chang
AU - X. Bao
AU - A. D. Cox
AU - T. L. Ratliff
AU - C. Conrad
AU - M. Fishel
AU - M. Flick
AU - N. A. Lanman
AU - B. D. Elzey
AU - B. Han
PY - 2026
DA - 2026/06/25
PB - bioRxiv
DO - 10.64898/2026.06.25.734662
UR - https://www.biorxiv.org/content/10.64898/2026.06.25.734662v4
AB - 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. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained 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 interrogate this axis mechanistically, we integrated human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models that reconstruct tumor-stroma interactions under controlled coagulation exposure, followed by cross-scale validation in vivo. 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 MPTS 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 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.
ER -