Investigation of the mitochondrial function in GNAS mutant neoplasms

GNAS 突变肿瘤中线粒体功能的研究

• 批准号: 10396962
• 负责人: Krushna Chandra Patra
• 金额: $ 19.52万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396962
• 关键词: Acetyl Coenzyme A; Address; Amino Acid Metabolism Pathway; Biological Assay; Biological Models; Branched-Chain Amino Acids; Cells; Citric Acid Cycle; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Development; Equilibrium; Exhibits; FADH2; Fatty Acids; Foundations; GTP-Binding Proteins; Genetic; Genetically Engineered Mouse; Gnas protein; Goals; Growth; Hot Spot; Human; Implant; Investigation; Lead; Lipids; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Maps; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microscopy; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Mutation; NADH; Neoplasms; Normal Cell; Normal tissue morphology; Nutrient; Oncogenes; Oncogenic; Organoids; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacology; Physiological Processes; Process; Production; Protein Subunits; Proteins; Proteome; Proteomics; Publishing; Reaction; Recurrence; Regulation; Role; Series; Signal Pathway; Signal Transduction; Solid; Structure; Testing; Therapeutic; Up-Regulation; aerobic glycolysis; amino acid metabolism; base; cancer cell; cancer subtypes; cancer type; experimental study; fatty acid oxidation; gain of function mutation; innovation; metabolomics; mitochondrial metabolism; mutant; neoplastic cell; new therapeutic target; pancreatic tumorigenesis; patient population; preclinical study; programs; protein expression; salt-inducible kinase; subcutaneous; targeted treatment; tumor; tumor growth; tumor initiation; tumorigenesis

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.

越来越多的证据表明，在肿瘤发生过程中需要线粒体的功能，但 线粒体状态在不同的致癌突变中是如何改变的，目前还很不清楚。中的更改 线粒体的代谢和功能是线粒体动力学(分裂/融合)的结果，并被重塑 线粒体蛋白质组。CAMP/PKA通路在线粒体功能调节中的保守作用 以及各种生理过程中的动态变化。这项建议的目标是全面分析 胰腺癌中携带功能获得突变的一组患者的线粒体功能和状态 GNAS(~60%)。在最近的一项研究中，我发现突变的GNAS激活cAMP/PKA途径，从而导致 失活盐诱导激酶(SIKs)和重新连接代谢过程，这是 这些肿瘤的肿瘤生长。全球多重蛋白质组学数据显示细胞选择性重塑 通过突变的GNAS激活的蛋白质组。具体地说，存在脂肪酸氧化浓缩蛋白(粮农组织) 和支链氨基酸(BCAA)途径，它们在线粒体中被分割。基座 关于这些初步数据和cAMP/PKA在控制线粒体动力学和 关于新陈代谢，我假设线粒体在突变的GNAS的肿瘤形成过程中发挥着深远的作用。 在坚实的基础上，这项K22提案旨在绘制GNAS-PKA-SIK在 线粒体动力学和蛋白质组学图景。它将检验这样一种假设，即动态变化和 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 突变的肿瘤。使用最先进的细胞器纯化，蛋白质组学，代谢示踪和与 胰腺癌类器官的功能分析；我试图确定线粒体在GNAS中的关键功能 突变癌症。这些研究的结果将给我们对致癌cAMP信号的无与伦比的理解 癌症，并可能导致新的靶向治疗的开发，可用于基因定义的患者 人口。