A systems-metabolism approach to identify mitochondria-dependent vulnerabilities in colorectal cancer

识别结直肠癌中线粒体依赖性脆弱性的系统代谢方法

• 批准号: 10703479
• 负责人: David Francis Kashatus
• 金额: $ 38.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703479
• 关键词: Acetyl Coenzyme A; Address; Anabolism; Area; Bacteria; Biochemical Pathway; Butyrates; Cellular Metabolic Process; Circulation; Citric Acid Cycle; Colorectal Cancer; Complex; Computer Models; Data; Dependence; Dietary Intervention; Environment; Event; Exhibits; Exposure to; Feeds; Generations; Glycolysis; Growth; HCT116 Cells; Hepatic; Hepatocyte; Heterogeneity; Human; Injections; Inner mitochondrial membrane; KRAS oncogenesis; KRAS2 gene; Liver; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammalian Cell; Membrane; Membrane Potentials; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Microbe; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Mutation; Neoplasm Metastasis; Nutrient; Oncogenes; Oncogenic; Organelles; Oxidative Phosphorylation; Pancreatic Ductal Adenocarcinoma; Patients; Primary Neoplasm; Process; Proliferating; Publishing; Reaction; Research Project Grants; Role; Shapes; Signal Transduction; Site; Stress; Structure; Surface; System; Systems Analysis; Systems Biology; Testing; Tissues; Tumor Promotion; Volatile Fatty Acids; Work; Xenograft procedure; adenoma; cancer cell; cancer initiation; colon cancer cell line; colorectal cancer metastasis; fatty acid metabolism; gut bacteria; gut microbiota; host microbiota; human model; in vivo; knowledge integration; liver metabolism; metastatic colorectal; nutrient metabolism; predictive modeling; programs; tumor; tumor growth; tumor heterogeneity; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis

PROJECT ABSTRACT/SUMMARY During tumorigenesis, mitochondrial function is altered by fusion/fission dynamics that control organelle structure and impact overall cell metabolism. Signaling from oncogenic RAS fragments mitochondrial tubules and causes metabolic changes that support tumor growth. However, the precise role of these oncogene- driven mitochondrial changes on cancer metabolism is unclear, especially when considering the diverse metabolic environments in which tumors develop. For example, colorectal cancer (CRC) initiates in the gut where the microbiota produces high quantities of short chain fatty acids (SCFAs) that are metabolized by normal colonocytes. During CRC tumorigenesis, mutations in the KRAS oncogene occur at the transition to adenomas, suggesting that mitochondrial adaptation in the gut may be critical for progression of primary tumors. And yet, the primary site of CRC metastasis is the liver, which provides a very different set of nutrients for metabolism and growth. Recognizing the complexity of metabolic networks both inside and outside a developing tumor, we propose a systems biology approach to examine the role of RAS-induced mitochondrial fission in CRC. Specifically, our objective is to identify metabolic adaptations that permit mitochondrially fragmented CRC cells to grow in the unique metabolic environment of the gut and metastatic CRC cells to grow in the liver. While the fragmentation of the mitochondrial network can impact tumor metabolism in multiple ways, we hypothesize that RAS-induced mitochondrial fragmentation leads to hyper- compartmentalization of specific metabolic reactions within the mitochondrial matrix that depend on low- abundance mitochondrial proteins. We predict that these adaptations create unique vulnerabilities in CRC cells as they switch from normal SCFA metabolism to promote biosynthesis and energy generation. The specific aims are to 1) curate a metabolic model of human CRC cells that incorporates the system-wide impact of mitochondrial fragmentation and the availability of microbe-derived SCFAs; 2) instantiate metabolic models of CRC with data characterizing in vivo metabolic states to assess impacts of gut microbiota metabolism and mitochondrial fragmentation; and 3) evaluate the impact of metabolic adaptations to mitochondrial organelle stress on CRC colonization and growth as liver metastases. Successful completion of this project will provide a better understanding of CRC metabolism that may one day point to dietary interventions or shifts in the gut microbiota that predictably influence organelle adaptation.

项目摘要/总结 在肿瘤发生过程中，控制细胞器的融合/裂变动力学改变了线粒体功能 结构并影响整体细胞代谢。致癌 RAS 信号传导使线粒体小管断裂 并引起支持肿瘤生长的代谢变化。然而，这些癌基因的确切作用- 驱动线粒体变化对癌症代谢的影响尚不清楚，特别是考虑到多种因素时 肿瘤生长的代谢环境。例如，结直肠癌 (CRC) 始于肠道 其中微生物群产生大量的短链脂肪酸 (SCFA)，这些脂肪酸被代谢 正常结肠细胞。在 CRC 肿瘤发生过程中，KRAS 癌基因突变发生在向 腺瘤，表明肠道中的线粒体适应可能对于原发性腺瘤的进展至关重要 肿瘤。然而，结直肠癌转移的主要部位是肝脏，它提供了一组非常不同的营养物质 用于新陈代谢和生长。认识到体内和体外代谢网络的复杂性 发展中的肿瘤，我们提出了一种系统生物学方法来检查 RAS 诱导的线粒体的作用 CRC 中的裂变。具体来说，我们的目标是确定允许线粒体的代谢适应 破碎的结直肠癌细胞在肠道独特的代谢环境中生长，转移性结直肠癌细胞 生长在肝脏中。虽然线粒体网络的碎片化会影响肿瘤代谢 通过多种方式，我们假设 RAS 诱导的线粒体断裂会导致过度 线粒体基质内特定代谢反应的区室化取决于低 丰富的线粒体蛋白。我们预测这些调整会在 CRC 中造成独特的脆弱性 细胞从正常的 SCFA 代谢转变为促进生物合成和能量产生。这 具体目标是 1) 建立一个包含全系统影响的人类 CRC 细胞代谢模型 线粒体碎片和微生物来源的 SCFA 的可用性； 2）实例化代谢模型 CRC 的数据表征体内代谢状态，以评估肠道微生物群代谢的影响和 线粒体碎裂； 3）评估代谢适应对线粒体细胞器的影响 对结直肠癌定植和肝转移生长的压力。该项目的成功完成将提供 更好地了解结直肠癌代谢，有一天可能会指出饮食干预或肠道变化 可预测地影响细胞器适应的微生物群。