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Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid cancers and is associated with very low overall and progression-free survival rate. Clinically, PDAC patient tumors show high expression levels of multiple components of the coagulation system (e.g., tissue factor, etc.) and fibrinolytic system, including urokinase plasminogen activator (uPA) and receptor (uPAR). In addition, pancreatic cancer patients show elevated levels of circulating fibrinogen (Fib) and the fibrin degradation product D-dimer in plasma, with increased correlation in patients with distant metastasis. We hypothesized that targeting the plasminogen activation system components would disrupt PDAC tumor progression. Using pancreatic cancer cell lines from the KPC mouse model (K-rasLSL.G12D/+; p53LSL.R172H/+; Elas-CreER), individual components of the fibrinolytic system (uPA and uPAR) were eliminated using CRISPR-Cas9 technology. Knocking out uPA and uPAR in KPC cells resulted in significantly smaller tumors relative to Cas9 control tumors. Compared to WT mice, KPC murine pancreatic cancer cells injected orthotopically in Plg-/- mice had significantly attenuated tumor growth, suggesting the pro-tumor effect of tumor cell-derived uPA/uPAR expression was linked at least in part to plasmin(ogen) activation to enhance PDAC tumor progression. To further investigate the contribution of Plg or Fib in the microenvironment in PDAC progression, we used Plg or Fib specific antisense oligonucleotide (ASO) treatment to specifically deplete plasminogen or fibrinogen levels in mice bearing human PDAC tumors. Treatment with Plg-ASO or Fib-ASO significantly decreased tumor burden in both orthotopic and subcutaneous models bearing human tumors. Bioluminescent imaging revealed that Plg-ASO and Fib-ASO treatment also decreased the spontaneous metastatic burden. Histological analysis of lung and liver tissue from Plg-ASO-treated mice confirmed reduced metastatic burden of the primary tumor, especially to the lungs. Similarly, Fib-ASO-treated mice had significantly lower metastatic burden in both liver and lung tissues. Our data demonstrate that depleting Plg or Fib in circulation reduces tumor growth and metastasis. Collectively, our data suggests the PA system is important to both tumor growth and metastasis. Based on our findings with Plg depletion, the unexpected finding that depletion of the plasmin target fibrin(ogen) in the microenvironment also significantly reduces primary tumor growth and metastasis suggests plasmin(ogen) may function through fibrin(ogen)-independent mechanisms to promote PDAC progression. Citation Format: Nayela N. Chowdhury, Yi Yang, Yingnan Shen, Silpa Gampala, Olivia Babb, Bumsoo Han, Alisa S. Wolberg, Matthew J. Flick, Melissa L. Fishel. Unraveling the role of the fibrinolytic system in pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2447. |
