Abstract PO-127: A uPA/uPAR axis in both the tumor cell and stromal compartment drives PDAC disease progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid tumor malignancy with a 5-year survival rate of 9%. In both patients and animal models of disease, PDAC is associated with robust coagulation system activity. Intriguingly, in addition to being a rich source of procoagulant factors, PDAC tumors highly express fibrinolytic system components. Supporting this concept, urokinase plasminogen activator (uPA) and uPA receptor (uPAR) expression positively correlates with reduced overall patient survival. Here, we tested the hypothesis that the expression and activity of plasminogen activation (PA) system components are functionally linked to PDAC tumor growth and disease progression. We generated C57Bl/6-derived KPC (i.e., KRasG12D, TRP53R172H) PDAC cell lines in which uPA and uPAR were knocked out using CRISPR-Cas9. We then analyzed orthotopic tumor growth and experimental metastasis in mice carrying null or functional mutations in uPA, uPAR, or plasminogen to evaluate the interplay of PA components derived from tumor cells and/or stromal cells in mediating PDAC progression. Although both KPC cell CRISPR variants retained procoagulant function, elimination of tumor cell uPA or uPAR yielded significantly smaller tumors when compared to Cas9 control tumor cells in wildtype mice. Similarly, the growth of WT KPC tumor cells in C57Bl/6 background uPA-KO or uPAR-KO mice also resulted in reduced tumor growth. To our surprise, the metastasis potential of WT KPC tumor cells in uPA-KO or uPAR-KO mice did not change when compared to wildtype mice. Regarding to the uPA/uPAR axis downstream effector plasminogen, the growth of WT KPC tumors in plasminogen-KO mice was also significantly reduced, but not to the same extent as when eliminating uPA or uPAR. In addition, eliminating plasminogen drastically reduced WT KPC tumor cells metastasis potential. In conclusion, our data suggest a mechanism whereby uPA functions through uPAR in both the tumor cell and stromal cell compartments to promote PDAC progression through plasminogen-dependent and -independent mechanisms. Citation Format: Yi Yang, Sara R. Abrahams, Aditi Kothari, Harshi Matada, Keely Davey, Alisa S. Wolberg, Matthew J. Flick. A uPA/uPAR axis in both the tumor cell and stromal compartment drives PDAC disease progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-127.