Transfer: Elucidating the Mechanism of Ga13 Mediated Tumor Suppression in Pancreatic Cancer

RESEARCH SUMMARY The heterotrimeric G proteins transduce signals from the G protein-coupled receptors (GPCRs), the largest class of cell surface proteins that regulate a wide variety of biological processes. Ga13, a member of the G12 family of heterotrimeric G proteins, has been reported to be a tumor suppressor or promoter in different tumor contexts. We recently reported that loss of Ga13 accelerated tumor development and reduced survival in a well- characterized genetic mouse model of pancreatic cancer. Mechanistically, Ga13-deficient mouse pancreatic tumors had elevated mTOR signaling, similar to human pancreatic cancer. Consistently, tumors derived from Ga13-deficient pancreatic cancer cells were susceptible to rapamycin, a well-characterized mTOR inhibitor. Recently, we have shown that loss of Ga13 in pancreatic tumors and cancer cells increased mitochondrial metabolism and expression of inflammatory cytokines. However, the impact of tumor metabolism and inflammation on the development and progression of Ga13-deficient tumors and whether mTOR signaling regulates these processes has not been investigated. Our objective in this application is to elucidate the mechanism(s) by which the deletion of Ga13 in the pancreas cancer cells contributes to tumor development and progression in vivo. The central hypothesis is that loss of Ga13 promotes tumor development through elevated mTOR signaling to drive mitochondrial metabolism and inflammation. Two specific aims are proposed: 1) Determine whether mTORC1 signaling is necessary for promoting cellular metabolism of Ga13-deficient pancreas tumors. 2) Determine whether mTORC1 signaling is essential in mediating the increased inflammation in Ga13- deficient tumors. In Aim 1, we will determine whether inhibition of mTORC1 signaling delays tumor development and induces cell death in early and advanced tumors lacking Ga13. Further, we will assess how Ga13 loss regulates tumor metabolism and whether Ga13-deficient tumors are susceptible to perturbations of mitochondrial functions. In Aim 2, we will determine whether Ga13 loss increases inflammatory cytokine levels and tumor- promoting immune cells in early and advanced tumors. We will determine whether blocking mTORC1 signaling limits the expression of candidate cytokines and immune cell infiltration to suppress tumor growth in Ga13 lacking tumors. Finally, we will examine whether combining anti-inflammatory agents with inhibitors of mitochondrial function will synergistically enhance anti-tumor efficacy. The innovative component of this proposal is the use of a unique mouse model to study the tumor suppressive function of Ga13, where the loss of the gene in both human and mouse pancreas tumors correlates with elevated mTOR signaling and worse survival outcome. We will also use the innovative approach of human tumor slice culture assays to determine whether Ga13 status dictates the response to inhibition of mTORC1 signaling. The proposal is significant because it will elucidate the tumor suppressive mechanisms of Ga13 in pancreatic cancer, providing insights into beneficial therapies for patients with Ga13 deficiency.