Investigation of the mitochondrial function in GNAS mutant neoplasms

新出现的证据指出在肿瘤发生过程中需要线粒体功能，但 线粒体状态在不同的致癌突变中是如何改变的，这在很大程度上是不清楚的。变化 线粒体代谢和功能是线粒体动力学（裂变/融合）和重塑的结果。 线粒体蛋白质组cAMP/PKA通路在线粒体功能调节中具有保守性作用 和各种生理过程中的动力学。该提案的目标是全面分析 线粒体功能和状态在胰腺癌的一个子集，这些港口获得性功能突变， GNAS（~60%）。在最近的一项研究中，我发现突变的GNAS激活cAMP/PKA通路，导致 失活盐诱导激酶（SIKs）和重新布线代谢过程，这是 这些肿瘤的生长。全球多重蛋白质组学数据显示， 蛋白质组的突变体GNAS激活。特别是脂肪酸氧化富集蛋白（FAO） 和支链氨基酸（BCAA）途径，其在线粒体中被区室化。基于 基于这些初步数据和cAMP/PKA在控制线粒体动力学中的关键作用， 代谢，我假设线粒体在突变GNAS的肿瘤发生过程中具有深远的作用。 在坚实的基础上，这一K22提案旨在绘制GNAS-PKA-SIK介导的变化， 线粒体动力学和蛋白质组学。它将测试的假设，在动态和 蛋白质组重构导致FAO和BCAA途径功能改变，这是GNAS生长所必需的 突变肿瘤使用最先进的细胞器纯化，蛋白质组学，代谢追踪， 胰腺癌类器官中的功能测定;我试图确定GNAS中线粒体的关键功能 突变型癌症这些研究的结果将使我们对肿瘤细胞中致癌cAMP信号传导有前所未有的了解。 并可能导致新的靶向治疗的发展，可用于基因定义的患者 人口。

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.