Abstract
Protease activated receptor-1 (PAR1) expression is associated with disease progression and overall survival in a variety of cancers. However, the importance of tumor cell PAR1 in pancreatic ductal adenocarcinomas (PDAC) remains unexplored. Utilizing orthotopic models with wild type and PAR1-targeted PDAC cells, we show that tumor cell PAR1 negatively affects PDAC growth, yet promotes metastasis. Mechanistically, we show that tumor cell-specific PAR1 expression correlates with mesenchymal signatures in PDAC and that PAR1 is linked to the maintenance of a partial mesenchymal cell state. Indeed, loss of PAR1 expression results in well-differentiated pancreatic tumors in vivo, with enhanced epithelial characteristics both in vitro and in vivo. Taken together, we have identified a novel growth inhibitory role of PAR1 in PDAC, which is linked to the induction, and maintenance of a mesenchymal-like phenotype. The recognition that PAR1 actively limits pancreatic cancer cell growth suggest that the contributions of PAR1 to tumor growth differ between cancers of epithelial origin and that its targeting should be applied with care.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with an extremely low survival rate (5-year survival ~7.7%) [1, 2]
Previous work on Protease activated receptor-1 (PAR1) has demonstrated a role for PAR1 in tumor progression in different tumor types leading to poor prognosis in patients with high PAR1 expression levels [17, 21, 22, 25, 26]
Given that PAR1 expression in these sets is the cumulative expression obtained from tumor cells, stromal content, and possibly adjacent non-tumor tissue, we reasoned that further analyses should address if PAR1 signaling in tumor and stromal compartments contribute differently to tumor growth
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with an extremely low survival rate (5-year survival ~7.7%) [1, 2]. This high mortality rate is largely due to late diagnosis with the vast majority of patients presenting with locally advanced or metastatic disease, and only around 20% of the patients are eligible for surgical resection. The only noteworthy progress has been in lowering mortality rates for patients undergoing resections, and a small prolongation and improved quality of life in patients with unresectable disease by chemotherapeutic agents [3]. A key factor responsible for the poor prognosis in PDAC is a high propensity for epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells [6]. Suppression of EMT enhances therapeutic efficacy and survival in a murine pancreatic cancer model [15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
