Abstract PO-094: Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition

Abstract Gα13 transduces signals from G protein-coupled receptors. Gα13 is pro-tumorigenic in epithelial cancer cell lines, which contrasts with its tumor-suppressive function in transgenic mouse models of lymphomas. We investigated the role of Gα13 in pancreatic tumor development and progression in a transgenic mouse model. Here we show that while loss of Gα13 in pancreatic cell lines decreases tumor growth in vivo, Gα13 loss in the Kras-driven (KC) mouse model of pancreatic tumor initiation does not affect tumor development or survival. Instead, Gα13 loss in the Kras/Tp53 (KPC) transgenic mouse model of advanced pancreatic cancer promotes well-differentiated tumors with increased tumor burden and reduced survival. Mechanistically, Gα13 loss in the KPC mouse model enhances E-cadherin-mediated cell-cell junctions and mTOR signaling. Gα13-deficient pancreatic cancer cell lines derived from these mice form well-differentiated tumors, which are susceptible to mTOR inhibition with rapamycin. Importantly, human pancreatic cancers with low Gα13 expression also exhibit increased E-cadherin protein expression and mTOR signaling. This work establishes a context-dependent role of Gα13 in pancreatic tumorigenesis, demonstrating a tumor-suppressive role in transgenic mouse models of advanced pancreatic cancer. Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao N. D. Pham, Hidayatullah G. Munshi. Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition [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-094.