Metabolic liabilities of cancer cells to the tumor nutrient environment

癌细胞对肿瘤营养环境的代谢负担

• 批准号: 9414918
• 负责人: Kivanc Birsoy
• 金额: $ 13万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414918
• 关键词: Address; Atlas of Cancer Mortality in the United States; Biological Assay; CRISPR/Cas technology; Cancer Cell Growth; Cancer cell line; Cell Culture System; Cell Line; Cell Respiration; Cells; Cholesterol; Chronic; Collection; Consumption; DNA; Defect; Dependence; Encyclopedias; Environment; Exposure to; Gene Expression; Genes; Genetic; Genomics; Glucose; Growth; Guide RNA; In Vitro; Libraries; Low-Density Lipoproteins; Malignant Neoplasms; Maps; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondrial DNA; Molecular; Mutation; Nutrient; Oxidative Phosphorylation; Oxygen Consumption; Pathway interactions; Prevalence; RNA library; Reporting; Role; Supplementation; System; Technology; Testing; Time; Tumorigenicity; Waste Products; Work; Xenograft procedure; cancer cell; cancer therapy; cell growth; design; experimental study; extracellular; in vivo Model; loss of function; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; mutant; nutrient deprivation; pressure; programs; public health relevance; response; screening; targeted treatment; therapy design; tissue culture; tool; tumor; tumor growth; tumor initiation; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis; uptake

 DESCRIPTION (provided by applicant): It has recently become evident that cancer cells rewire their metabolism to meet their demands of proliferation and survival. Metabolic changes are dictated in part by the tumor nutrient environment as cancer cells are frequently starved for nutrients and exposed to toxic waste products due to a combination of increased nutrient consumption and dysfunctional vasculature. While the components of most metabolic pathways have long been described, it remains poorly understood how the flow of metabolites is rewired in the nutrient environment of tumors. I have recently developed two technologies to enable study of cancer cells in a tumor-like nutrient environment: a continuous flow cell culture system for maintaining reduced but steady nutrient concentrations (nutrostat) and a DNA-barcoded cell competition assay for simultaneously measuring the growth of pooled cancer cell lines cultured in the nutrostats. Focused on low glucose, these technologies enabled us to systematically investigate the cancer metabolic dependencies and discovered that most cancer cells reversibly switch to a more oxidative metabolism under low glucose conditions. However, a subset of cancers cells with heteroplasmic loss-of-function mtDNA mutations are unable to increase their oxygen consumption in low glucose conditions. This inability to induce oxidative metabolism hampers cell growth in the glucose-poor tumor environment and suggests the existence of a stronger positive selection for persistence of such mtDNA mutations. Supporting this notion, the prevalence of truncating mutations in mtDNA-encoded OXPHOS components is reported to be as high as 65%. It is, however, unclear why such a high percentage of cancer cells accumulate mtDNA mutations and how these mutations can be exploited as a liability for designing therapies. In this proposal, building on my previous observations, I aim to test the hypothesis whether heteroplasmic mtDNA mutations have functionally critical roles in tumorigenesis (Aim1) and confer metabolic liabilities that can be exploited for therapy (Aim2). Additionally, existence of metabolic vulnerabilities of cancer cells to low glucose calls for a more comprehensive examination of other nutrient dependencies. Therefore, as an extension to these aims, I will map the cancer nutrient dependencies using our DNA-barcoded cell competition assay (Aim3).

 描述（由申请人提供）：最近已经变得明显的是，癌细胞重新调整其代谢以满足其增殖和存活的需求。代谢变化部分由肿瘤营养环境决定，因为癌细胞经常缺乏营养并暴露于有毒废物，这是由于营养消耗增加和脉管系统功能障碍的组合。虽然大多数代谢途径的组成部分早已被描述，但对代谢物的流动如何在肿瘤的营养环境中重新连接仍然知之甚少。我最近开发了两种技术，以使在肿瘤样营养环境中的癌细胞研究成为可能：用于维持降低但稳定的营养浓度的连续流动细胞培养系统（nutrostat）和用于同时测量在nutrostat中培养的合并癌细胞系的生长的DNA条形码细胞竞争测定。专注于低葡萄糖，这些技术使我们能够系统地研究癌症代谢依赖性，并发现大多数癌细胞在低葡萄糖条件下可逆地切换到更氧化的代谢。然而，具有异质性功能丧失mtDNA突变的癌细胞亚群在低葡萄糖条件下不能增加其耗氧量。这种不能诱导氧化代谢的能力阻碍了细胞在葡萄糖缺乏的肿瘤环境中的生长，并表明存在更强的阳性选择，使这种mtDNA突变持续存在。支持这一观点的是，据报道mtDNA编码的OXPHOS组分中截短突变的发生率高达65%。然而，目前尚不清楚为什么如此高比例的癌细胞会积累mtDNA突变，以及如何利用这些突变来设计治疗方法。 在这个提议中，基于我以前的观察，我的目标是检验异质性mtDNA突变是否在肿瘤发生中具有功能关键作用（Aim1）并赋予可用于治疗的代谢责任（Aim2）。此外，癌细胞对低葡萄糖的代谢脆弱性的存在要求对其他营养依赖性进行更全面的检查。因此，作为这些目标的延伸，我将使用我们的DNA条形码细胞竞争测定（Aim3）来绘制癌症营养依赖性。

项目成果

CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4.

• DOI: 10.1016/j.molcel.2019.01.037
• 发表时间: 2019-04
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Xiphias Ge Zhu;Shirony Nicholson Puthenveedu;Yihui Shen;Konnor C. La;C. Ozlu;Tim Wang;Diana Klompstra;Yetis Gultekin;Jingyi Chi;Justine Fidelin;Tao Peng;H. Molina;H. Hang;Wei Min;Kıvanç Birsoy