Abstract LB453: Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer

Abstract Host inflammation and tumor-driving genetic alterations significantly influence the immune microenvironment of pancreatic cancer. Indeed, chronic pancreatitis (CP) is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), which is characterized by an early inflammatory response that evolves with tumor initiation and progression. Our previous work highlighted the role of the Pdk1/mTOR signaling axis in promoting pancreatic cancer development, particularly after genetic ablation of Gα13, a heterotrimeric G-protein frequently dysregulated in human tumors. To further investigate how Gα13 modulates the inflammatory response in both pancreatitis and pancreatic cancer, we employed mouse models to examine its role in inflammatory cytokines expression and mTOR signaling. We found that pancreas-specific loss of Gα13 exacerbated tissue injury, elevated pro-inflammatory cytokines, and increased macrophage recruitment in models of pancreatitis. Additionally, loss of Gα13 promoted mTOR signaling in these models, mirroring our earlier findings in pancreatic cancer. Interestingly, while mTOR inhibition alleviated tissue damage and suppressed inflammation in acute pancreatitis, it had no effect in the chronic phase. These findings align with our analysis of human tissue samples, where Gα13 expression was significantly reduced only in acute pancreatitis. Furthermore, in Gα13-deficient tumors, mTOR inhibition suppressed inflammatory cytokine expression and hindered tumor progression. Notably, targeting Pdk1 signaling resulted in a stronger anti-tumor response, with evidence for collagen remodeling and enhanced adaptive immune response. Overall, our findings uncover a novel, targetable pathway regulating both inflammation and tumor progression in pancreatic cancer, which could offer therapeutic opportunities depending on the G-protein status in patients. Citation Format: Khadijeh Karbalaei, Anastasia E. Metropulos, Khulood Alzahrani, Apurba Majumder, Thao N. Pham, Hidayatullah G. Munshi, Mario A. Shields. Elucidating the signaling mechanisms of Galpha13-mediated inflammation and tumor suppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB453.