Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells

Ras 驱动的癌细胞代谢脆弱性的鉴定

基本信息

批准号：
8370625
负责人：
JOSHUA D RABINOWITZ
金额：
$ 46.65万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-07 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8370625
关键词：
Acetyl Coenzyme A Allografting Amino Acids Anabolism Autophagocytosis Biological Models Bladder Cancer Cell Growth Cancer Model Cancer cell line Cells Citric Acid Cycle Collaborations Colorectal DNA Dependence Development Digestion Enzymes Event Fatty Acids Fermentation Funding Genetic Genetically Engineered Mouse Glucose Glutamine Grant Growth HRAS gene Human Impairment In Vitro Isotopes K-ras mouse model Knockout Mice Laboratories Lung Malignant Neoplasms Mass Spectrum Analysis Measurement Membrane Metabolic Metabolic Pathway Metabolic stress Metabolism Monitor Mus Mutate Non-Small-Cell Lung Carcinoma Normal Cell Oncogene Activation Oncogenes Oncogenic Organelles Oxygen Pancreas Pathway interactions Phosphotransferases Process Production Protein Biosynthesis Proteins Proteomics RAS genes RNA Research Role Signal Transduction Signaling Protein System Testing Time Tracer Tumor Suppressor Genes United States National Institutes of Health Universities Warburg Effect addiction aerobic glycolysis cancer cell cancer therapy enzyme activity glucose production human MAP3K1 protein in vivo inhibitor/antagonist liquid chromatography mass spectrometry meetings metabolomics mouse model neoplastic cell new therapeutic target outcome forecast tissue culture transcriptomics tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells Tumor growth requires biosynthesis of protein, DNA, RNA, and membrane. Cellular metabolism provides the substrates and energy for this biosynthesis. Consistent with the central role of metabolism in cancer growth, altered metabolism is a hallmark of cancer. The best-known example is avid glucose fermentation even in the presence of oxygen, i.e., the "Warburg effect". Recently, it has become clear that a major function of oncogenes is to induce metabolic changes, including the Warburg effect, to provide substrates and energy for biosynthesis that enables tumor growth. Thus cancer cells are vulnerable to interference in metabolic pathways, hence the need to target metabolism for cancer therapy. Ras genes are among the most frequently mutated oncogenes in cancer, and their mutational activation induces the Warburg effect. Unlike for many oncogenic signaling proteins, there are no safe and effective pharmacological inhibitors of activated Ras, increasing the importance of understanding metabolic vulnerabilities of Ras-driven tumors. We have recently examined the metabolic consequences of Ras activation in tumor cells via metabolomics and isotope-tracer studies. This revealed that Ras not only induces aerobic glycolysis, but also decreases acetyl-CoA production from glucose and fatty acids, and enhances dependence of the TCA cycle on glutamine, revealing a metabolic vulnerability. Moreover, we found that Ras activates the catabolic cellular self-digestion process of autophagy, that autophagy sustains TCA cycle metabolism, and that tumor cells with activated Ras are dependent on autophagy for survival and tumorigenesis. Thus, activated Ras leads to autophagy addiction, revealing another metabolic vulnerability. Our unifying hypothesis is that Ras decreases input into the TCA cycle from glucose and fatty acids, creating the requirement for glutamine and other autophagy-supplied TCA cycle substrates to sustain tumor cell metabolism. Here we aim to test this hypothesis and understand more comprehensively the underlying mechanisms, generality of the metabolic alterations induced by Ras and the best ways to exploit them. To this end we will combine state-of-the-art metabolomics with in vitro and in vivo cancer models driven by Ras or the downstream kinases Akt and Raf. The net effect of this research will be to dramatically increase understanding of the interplay of oncogene signaling and metabolism, and in so doing to identify new therapeutic targets for Ras-driven cancers. This project is a direct extension of the very productive collaboration between the laboratories of Dr. Eileen White (Rutgers University) and Dr. Josh Rabinowitz (Princeton University) previously funded by a NIH Challenge Grant on cancer metabolism. PUBLIC HEALTH RELEVANCE: We have known for over 50 years that a major feature that distinguishes normal cells from cancer cells is altered metabolism. Only recently has it become clear that activation of oncogenes and loss of tumor suppressor genes reprograms metabolism to generate the building blocks for production of new tumor cells and to meet the energy requirements for cancer cell growth. Oncogenic forms of Ras dramatically alter cellular metabolism, promote tumorigenesis and are associated with poor prognosis. Targeting Ras therapeutically has been difficult, necessitating approaches to block pathways, such as metabolic pathways, downstream of Ras. We propose to use state-of-the-art mass spectrometry and cancer models to determine how Ras alters metabolism. This will expose vulnerabilities that can be exploited in the development of new cancer therapies.

描述（由申请人提供）：鉴定由Ras驱动的癌细胞的代谢脆弱性肿瘤生长需要蛋白质，DNA，RNA和膜的生物合成。细胞代谢为这种生物合成提供了底物和能量。与代谢在癌症生长中的核心作用一致，代谢改变是癌症的标志。最著名的例子是即使存在氧气，即“ Warburg效应”，即使存在狂热的葡萄糖发酵。最近，很明显，致癌基因的主要功能是诱导包括Warburg效应在内的代谢变化，以为生物合成提供底物和能量，以实现肿瘤生长。因此，癌细胞容易受到代谢途径的干扰，因此需要将代谢靶向癌症治疗。 RAS基因是癌症中最常见的肿瘤基因之一，它们的突变激活诱导了Warburg效应。与许多致癌信号蛋白不同，没有安全有效的药理学抑制剂的活化RAS，从而增加了理解RAS驱动肿瘤的代谢脆弱性的重要性。我们最近通过代谢组学和同位素跟踪研究研究了RAS激活在肿瘤细胞中的代谢后果。这表明RAS不仅诱导了有氧糖酵解，而且还降低了葡萄糖和脂肪酸的乙酰辅酶A产生，并增强了TCA循环对谷氨酰胺的依赖性，从而揭示了代谢脆弱性。此外，我们发现RAS激活自噬的分解代谢细胞自消化过程，即自噬可维持TCA循环代谢，并且具有活化RAS的肿瘤细胞取决于自噬的生存和肿瘤发生。因此，活化的RA会导致自噬成瘾，从而揭示了另一个代谢脆弱性。我们统一的假设是，RAS从葡萄糖和脂肪酸中降低了TCA周期的输入，从而对谷氨酰胺和其他自噬添加的TCA循环底物产生了要求，以维持肿瘤细胞代谢。在这里，我们旨在检验这一假设，并更全面地理解基本机制，RAS引起的代谢改变的一般性以及利用它们的最佳方法。为此，我们将将最先进的代谢组学与由RAS或下游激酶AKT和RAF驱动的体外和体内癌症模型相结合。这项研究的净效应将大大增加对癌基因信号传导和代谢相互作用的理解，并因此以确定针对RAS驱动的癌症的新治疗靶标。该项目直接扩展了Eileen White博士（Rutgers University）的实验室和乔什·拉比诺维茨（Josh Rabinowitz）（普林斯顿大学）的实验室之间非常有生产力的合作，此前由NIH挑战率提供了有关癌症代谢的挑战资助。公共卫生相关性：我们已经知道50多年来，将正常细胞与癌细胞区分开的主要特征是代谢改变的。直到最近，才清楚地表明，肿瘤基因的激活和抑制肿瘤基因的丧失重新编程了代谢，以生成生产新肿瘤细胞的基础，并满足癌细胞生长的能量需求。 Ras的致癌形式极大地改变了细胞代谢，促进肿瘤发生，并与预后不良有关。在治疗上靶向RAS一直很困难，需要采用阻断RAS下游的代谢途径等途径的方法。我们建议使用最先进的质谱和癌症模型来确定RAS如何改变新陈代谢。这将暴露在新的癌症疗法中可以利用的漏洞。