Oncotarget

Research Papers:

PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer

Cansu Tekin _, Kun Shi, Joost B. Daalhuisen, Marieke S. ten Brink, Maarten F. Bijlsma and C. Arnold Spek

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Oncotarget. 2018; 9:32010-32023. https://doi.org/10.18632/oncotarget.25880

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Abstract

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

Correspondence to:

Cansu Tekin, email: c.tekin@amc.uva.nl

Keywords: pancreatic cancer; PAR1; thrombin receptor; EMT

Received: March 09, 2018     Accepted: July 21, 2018     Published: August 10, 2018

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.


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