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

项目摘要/总结 在肿瘤发生过程中，线粒体功能被控制细胞器的融合/裂变动力学改变， 结构和影响整体细胞代谢。来自致癌RAS片段线粒体小管的信号传导 并导致支持肿瘤生长的代谢变化。然而，这些癌基因的确切作用- 线粒体变化对癌症代谢的驱动尚不清楚，特别是考虑到不同的 肿瘤生长的代谢环境。例如，结肠直肠癌（CRC）在肠道中起始 其中微生物群产生大量的短链脂肪酸（SCFA）， 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癌基因的过渡期。 这表明肠道中的线粒体适应可能对原发性结肠癌的进展至关重要。 肿瘤的然而，CRC转移的主要部位是肝脏，它提供了一套非常不同的营养素 新陈代谢和生长的关键认识到代谢网络的复杂性，无论是内部和外部， 发展中的肿瘤，我们提出了一个系统生物学的方法来研究RAS诱导的线粒体的作用， CRC中的裂变。具体来说，我们的目标是确定代谢适应， 片段化的CRC细胞在肠道和转移性CRC细胞的独特代谢环境中生长， 在肝脏中生长。虽然线粒体网络的断裂可以影响肿瘤的代谢， 多种方式，我们假设RAS诱导的线粒体片段化导致超 线粒体基质内的特定代谢反应的区室化依赖于低- 丰富的线粒体蛋白。我们预测，这些适应创造独特的脆弱性，在CRC 细胞，因为它们从正常的SCFA代谢转换到促进生物合成和能量产生。的 具体目标是：1）策划一个人类CRC细胞的代谢模型， 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， 线粒体碎片化; 3）评估代谢适应对线粒体细胞器的影响 强调CRC定植和生长为肝转移。该项目的成功完成将提供 更好地了解CRC代谢，可能有一天会指向饮食干预或肠道变化 微生物群可以预见地影响细胞器的适应。

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.