PROTEASE ACTIVATED RECEPTOR 1 (PAR-1) IN PANCREATIC CANCER EXPERIMENTAL METASTASIS

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, with a 5-year survival rate of only 2% for patients with metastasis, highlighting the need for new therapeutic strategies. Protease activated receptor-1 (PAR-1) is a G-protein coupled receptor, and previous studies demonstrated that PDAC tumor cells express high levels of PAR-1, contributing to tumor progression. To directly assess the contribution of PAR-1 to metastasis, mouse wildtype (KPC-Cas9) or PAR-1–deficient (KPC-PAR1KO) PDAC cancer cells were evaluated in a model of experimental metastasis. KPC-Cas9 cells formed significant numbers of macroscopically evident lung metastatic lesions whereas KPC-PAR-1KO cells displayed a significantly reduced metastatic burden. Mechanistic studies revealed PAR-1 loss does not affect initial adhesion of tumor cells to the lung vasculature or metastatic outgrowth. Rather, studies utilizing immunodeficient NSG mice revealed PAR-1 metastasis was driven in part by host immunity. Overall, study findings suggest that PAR-1 supports metastasis through both immune-dependent and independent mechanisms.