Mutant GNAS drives pancreatic tumorigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism

Abstract

G-protein α _s (GNAS) mediates receptor-stimulated cAMP signaling, which integrates diverse environmental cues with intracellular responses. GNAS is mutationally activated in multiple tumor types, although its oncogenic mechanisms remain elusive. We explored this question in pancreatic tumorigenesis where concurrent GNAS and KRAS mutations characterize pancreatic ductal adenocarcinomas (PDAs) arising from Intraductal Papillary Mucinous Neoplasms (IPMNs). By developing genetically engineered mouse models, we show that GNAS ^R201C cooperates with KRAS ^G12D to promote initiation of IPMN, which progress to invasive PDA following Tp53 loss. Mutant-GNAS remains critical for tumor maintenance in vivo. This is driven by protein kinase A-mediated suppression of salt-inducible kinases (SIK1-3), associated with induction lipid remodeling and fatty acid oxidation. Comparison of KRAS-mutant pancreatic cancer cells with and without GNAS mutations reveals striking differences in the functions of this network. Thus, we uncover GNAS-driven oncogenic mechanisms, identify SIKs as potent tumor suppressors, and demonstrate unanticipated metabolic heterogeneity among KRAS-mutant pancreatic neoplasms.