PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer
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Cansu Tekin1,2,3, Kun Shi1, Joost B. Daalhuisen1, Marieke S. ten Brink1, Maarten F. Bijlsma2,3,* and C. Arnold Spek1,*
1Amsterdam UMC, University of Amsterdam, Center of Experimental and Molecular Medicine, Amsterdam, The Netherlands
2Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, Amsterdam, The Netherlands
3Oncode Institute, Amsterdam, The Netherlands
*Authors share co-senior authorship
Cansu Tekin, email: firstname.lastname@example.org
Keywords: pancreatic cancer; PAR1; thrombin receptor; EMT
Received: March 09, 2018 Accepted: July 21, 2018 Published: August 10, 2018
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.
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