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

项目摘要/摘要 在肿瘤发生过程中，控制细胞器的融合/分裂动力学改变了线粒体的功能。 结构和影响整体细胞新陈代谢。致癌RAS片段线粒体管的信号转导 并导致支持肿瘤生长的新陈代谢变化。然而，这些癌基因的确切作用- 线粒体对癌症新陈代谢的影响尚不清楚，尤其是考虑到 肿瘤生长的代谢环境。例如，结直肠癌(CRC)始于肠道。 微生物群产生大量的短链脂肪酸(SCFA)，这些脂肪酸由 正常的结肠细胞。在结直肠癌的发生过程中，KRAS癌基因突变发生在向 腺瘤，提示肠道中线粒体的适应性可能是原发肿瘤进展的关键 肿瘤。然而，结直肠癌转移的主要部位是肝脏，它提供了一套非常不同的营养物质。 用于新陈代谢和生长。认识到企业内外代谢网络的复杂性 在肿瘤的发展过程中，我们提出了一种系统生物学的方法来检测RAS诱导的线粒体的作用 CRC中的裂变。具体地说，我们的目标是确定允许线粒体的新陈代谢适应 碎片化的CRC细胞在肠道独特的代谢环境中生长，并转移到 在肝脏里生长。而线粒体网络的断裂会影响肿瘤的新陈代谢 通过多种途径，我们假设RAS诱导的线粒体碎裂导致过度的- 线粒体基质中依赖低密度脂蛋白的特定代谢反应的区划 丰富的线粒体蛋白。我们预测，这些适应会在CRC中产生独特的漏洞 当细胞从正常的SCFA代谢转换到促进生物合成和能量产生时。这个 具体目标是：1)建立一个包含全系统影响的人类结直肠癌细胞代谢模型 线粒体碎裂和微生物来源的单链脂肪酸的可用性；2)实例化代谢模型 用表征体内代谢状态的数据来评估肠道微生物区系代谢的影响 线粒体碎裂；以及3)评估代谢适应对线粒体细胞器的影响 肝转移时强调结直肠癌的定植和生长。该项目的成功完成将提供 对结直肠癌新陈代谢的更好理解，有一天可能会指向饮食干预或肠道变化 可预测地影响细胞器适应的微生物区系。

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.