Investigation of the mitochondrial function in GNAS mutant neoplasms

Abstract public domain (NIH RePORTER)

Emerging evidences pointing out the requirement of mitochondrial function in the oncogenesis processes, but how the mitochondrial state is changed in different set of oncogenic mutations is largely obscure. Changes in mitochondrial metabolism and function are results of mitochondrial dynamics (fission/fusion) and remodeled mitochondrial proteome. cAMP/PKA pathway has conserved roles in the regulation of mitochondrial function and dynamics in various physiological processes. The goal of this proposal is to comprehensively analyze the mitochondrial function and state in a subset of pancreatic cancer those harbor gain-of-function mutations of GNAS (~60%). In a recent study I discovered mutant GNAS activates cAMP/PKA pathway that leads to inactivation salt-inducible-kinases (SIKs) and rewiring metabolic processes, a major mechanism required for tumor growth of these tumors. The global multiplex proteomics data revealed selective remodeling of cellular proteome by mutant GNAS activation. Specifically there is enrichment proteins of fatty acid oxidation (FAO) and branched chain amino acid (BCAA) pathways, which are compartmentalized in the mitochondria. Based on these preliminary data and the pivotal role of cAMP/PKA in controlling mitochondrial dynamics and metabolism, I hypothesize that mitochondria has profound roles in the oncogenesis process by mutant GNAS. Building on the solid foundation, this K22 proposal aims to map the GNAS-PKA-SIK mediated changes in mitochondrial dynamics and proteomic landscape. It will test the hypothesis that the changes in dynamics and proteome remodeling lead to altered FAO and BCAA pathway function, which are required for growth of GNAS mutant tumors. Using state-of-art organellar purification, proteomics, metabolic tracing and coupled with functional assays in pancreatic cancer organoids; I seek to identify the key function of mitochondria in GNAS mutant cancer. Results from these studies will give unparalleled understanding of oncogenic cAMP signaling in cancer and may lead to development of new-targeted therapies that can be used in genetically-defined patient populations.

Public health relevance public domain (NIH RePORTER)

Gain-of-function mutations in GNAS are observed in variety of human malignancies including pancreatic cancer. I have identified a core signaling network involving cAMP-PKA-SIK and metabolic program elicited by mutant GNAS that serves as its central oncogenic mechanism. This proposal aims at verifying a compelling hypothesis, that oncogenic GNAS rewires mitochondrial metabolism through remodeling mitochondrial proteome by controlling mitochondrial dynamics and that can be potential vulnerabilities to this genetic subtype of cancer. !