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

Oncotarget
Cansu TekinC Arnold Spek

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.

References

Jan 7, 2004·Cancer Cell·Sunil R HingoraniDavid A Tuveson
Sep 30, 2004·International Journal of Cancer. Journal International Du Cancer·Sorina Grisaru-GranovskyRachel Bar-Shavit
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jul 13, 2007·Gut·Paula GhanehJohn P Neoptolemos
Oct 23, 2008·Postgraduate Medical Journal·P GhanehJ P Neoptolemos
Jun 3, 2009·The Journal of Clinical Investigation·Raghu Kalluri, Robert A Weinberg
Apr 27, 2010·Pancreas·Emily L DeerSean J Mulvihill
Apr 20, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Frederiek F van DoormaalHarry R Buller
May 13, 2011·The New England Journal of Medicine·Thierry ConroyUNKNOWN PRODIGE Intergroup
Jun 28, 2011·The American Journal of Pathology·Jaroslaw CisowskiLidija Covic
Oct 20, 2011·Cancer Research·Maya ZiglerMenashe Bar-Eli
Jan 3, 2012·Current Molecular Medicine·Y WangM Li
May 12, 2012·Nature Reviews. Cancer·Thomas Brabletz
Aug 1, 2012·Oncology Letters·Na HanLisong Teng
Oct 18, 2013·The New England Journal of Medicine·Daniel D Von HoffMarkus F Renschler
Jan 18, 2014·International Journal of Cancer. Journal International Du Cancer·Karla C S QueirozC Arnold Spek
Jan 24, 2014·Journal of Surgical Oncology·Toshifumi MuraiYasuhiro Kodera
Aug 11, 2015·Frontiers in Oncology·Mohit Kumar JollyHerbert Levine
Mar 24, 2016·Oncotarget·Mohit Kumar JollyHerbert Levine
Jun 3, 2016·CA: a Cancer Journal for Clinicians·Kimberly D MillerAhmedin Jemal
Jul 2, 2016·Cell·M Angela NietoJean Paul Thiery
Nov 1, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jian WangS Perwez Hussain
Feb 12, 2017·Oncotarget·Weilong ZhongCheng Yang

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Citations

Nov 10, 2018·Journal of Thrombosis and Haemostasis : JTH·C A SpekM F Bijlsma
Aug 9, 2019·Journal of Thrombosis and Haemostasis : JTH·Anaum MaqsoodNigel Mackman
Feb 16, 2020·British Journal of Pharmacology·Krishna SriramPaul A Insel
Aug 19, 2020·Cellular Oncology (Dordrecht)·Cansu TekinC Arnold Spek
May 4, 2021·Blood·Derrick L TaoOwen J T McCarty
Jun 3, 2021·International Journal of Molecular Sciences·Aditi Kothari, Matthew J Flick

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Datasets Mentioned

BETA
GSE36133
GSE57083

Methods Mentioned

BETA
surgical resection
xenograft
flow cytometry
FCS
PCR
FACS
Cytomation
Assay

Software Mentioned

GSEA
GraphPad Prism
GraphPad
ImageJ
FLOWJO
LAS AF

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