Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

Abstract

SUMMARYGα13 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. 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. Importantly, human pancreatic cancers with low Gα13 expression 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.