Role of Tumor and Stromal Cell Metabolism in Stress Adaptation and Progression

肿瘤和基质细胞代谢在应激适应和进展中的作用

• 批准号: 7942941
• 负责人: Hilary A Coller
• 金额: $ 50万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942941
• 关键词: Address; Antineoplastic Agents; Apoptosis; Area; Autophagocytosis; Biochemical Pathway; Carbon; Catabolic Process; Catabolism; Cell Cycle; Cell Death; Cells; Consumption; Degradation Pathway; Employee Strikes; Energy Metabolism; Etiology; Event; Fibroblasts; Gene Expression; Genes; Glucose; Glycolysis; Growth; Homeostasis; Homologous Gene; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic stress; Metabolism; Molecular; Mutation; Necrosis; Normal Cell; Nucleic Acids; Nutrient; Organelles; Oxygen; Pathway interactions; Production; Protein Biosynthesis; Proteins; Proteome; Recovery; Recycling; Relapse; Role; Signal Transduction; Source; Stress; Stromal Cells; Stromal Neoplasm; Testing; Therapeutic; Translational Research; Tumor Biology; Tumor Tissue; Yeasts; aerobic glycolysis; angiogenesis; cancer cell; cancer therapy; cell growth; density; deprivation; drug discovery; neoplastic cell; notch protein; novel; novel strategies; oxidative damage; prevent; public health relevance; response; senescence; stress tolerance; treatment response; tumor; tumor growth; tumor progression; tumorigenesis; uptake

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-CA-112: Cancer Cell Energy Metabolism and Cancer Causation The molecular events that covert normal cells into tumor cells alter cellular metabolism to aerobic glycolysis, which favors macromolecular synthesis at the expense of efficient ATP production. This metabolic switch that facilitates tumor growth remains a fundamental distinction between normal and tumor cells that has yet to be effectively exploited of cancer therapy. Deregulated tumor cell growth and altered metabolism are also a source of metabolic stress. Oxygen, nutrient and factor deprivation caused by growth to high density and insufficient angiogenesis, and lactate production from glycolysis, are common features and sources of stress in the tumor microenvironment. How tumor and associated stromal cells respond to this stress effects tumor progression and treatment response. Possible responses include cell death (apoptosis or necrosis), cell cycle exit (quiescence or senescence) or adaptation and survival (autophagy). The catabolic process of autophagy is a lysosomal degradation pathway induced by metabolic stress that confers stress tolerance by maintaining energy homeostasis through cellular self-consumption and recycling, and by mitigating oxidative damage through the degradation of malfunctioning organelles and proteins. Autophagy may be particularly important to cells in a glycolytic state and under conditions of metabolic stress. Thus, the adaptation of tumor and associated stromal cells to metabolic stress is intimately linked to their inherent metabolic activity, but the role of metabolism in the context of tumor-stromal interaction is not known. Moreover, exactly how autophagy contributes to cellular metabolism and survival in the tumor microenvironment is not clear. We hypothesize that metabolic adaptation in tumor tissue allows prolonged survival to stress permitting tumor relapse and that discerning the underlying mechanisms will provide new approaches to cancer therapy. To test this hypothesis, we plan to define tumor and stromal cell metabolism, the role of catabolism through autophagy, and the mechanism of metabolic stress adaptation. Growth to high density induces fibroblasts to alter metabolism, activate autophagy, exit the cell cycle, and enter quiescence. We discovered that induction of quiescence of stromal fibroblasts dramatically alters gene expression, including activation of Notch signaling that is required for cell cycle reentry. Remarkably, glucose consumption and utilization is high in quiescent fibroblasts, which causes lactate secretion which can alter the microenvironment; but how does it influence tumorigenesis is not known. Analogous to quiescence in fibroblasts, apoptosis-defective tumor cells subjected to metabolic stress activate autophagy, exit the cell cycle and enter a state of prolonged dormancy from which they can reenter the cell cycle when growth conditions are favorable. We discovered that tumor cell dormancy dramatically alters the cellular proteome and gene expression with evidence of compensatory nutrient uptake, Foxo and Notch pathway activation, and induction of uncharacterized mammalian homologues of yeast genes required for quiescence induced by carbon source limitation. These findings suggest that major metabolic reprogramming accompanies the transition from proliferation to dormancy to cell cycle reentry. These striking parallels between quiescence and dormancy suggest that they are governed by common metabolic reprogramming events that may be a fundamental aspect of tumor biology that has yet to be explored. We propose to define the metabolic networks and role of metabolism as cells transition from proliferation to dormancy or quiescence to cell cycle reentry and how this alters tumor-stromal interaction. Preventing tumor cells from successful metabolic adaptation to stress enabling sustained dormancy and recovery may provide a novel approach to cancer therapy. Cancer cells acquire mutations that deregulate cell growth that also alter cellular metabolism. It has recently become apparent that the metabolic reprogramming of tumor cells is necessary to provide the building blocks for the macromolecular synthesis of proteins, lipids and nucleic acids necessary to support tumor cell growth. Importantly, these metabolic alterations distinguish tumor cells from normal cells, providing a potential therapeutic window and novel targets for anti-cancer drug discovery. PUBLIC HEALTH RELEVANCE: Cancer cells acquire mutations that deregulate cell growth that also alter cellular metabolism. It has recently become apparent that the metabolic reprogramming of tumor cells is necessary to provide the building blocks for the macromolecular synthesis of proteins, lipids and nucleic acids necessary to support tumor cell growth. Importantly, these metabolic alterations distinguish tumor cells from normal cells, providing a potential therapeutic window and novel targets for anti-cancer drug discovery.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，15-CA-112：癌细胞能量代谢代谢和癌症因果关系，覆盖正常细胞中肿瘤细胞的分子事件将细胞代谢改变至有氧糖酵解，有利于大分子合成，以有效的ATP产生为代价。这种促进肿瘤生长的代谢转换仍然是尚未有效利用癌症治疗的正常细胞和肿瘤细胞之间的基本区别。肿瘤细胞生长和代谢改变也是代谢应激的来源。氧气，养分和因子剥夺是由生长到高密度和血管生成不足以及糖酵解产生的乳酸引起的，是肿瘤微环境中的常见特征和应激源。肿瘤和相关的基质细胞如何应对这种应力影响肿瘤进展和治疗反应。可能的反应包括细胞死亡（细胞凋亡或坏死），细胞周期出口（静止或衰老）或适应和存活（自噬）。自噬的分解代谢过程是一种由代谢应力引起的溶酶体降解途径，通过通过细胞自我消耗和回收来维持能量稳态，通过维持能量稳态，通过降解氧化损害通过失功能细胞器和蛋白质来降低氧化损害。自噬可能对糖酵解状态和代谢应激条件下的细胞尤其重要。因此，肿瘤和相关的基质细胞对代谢应激的适应与其固有的代谢活性密切相关，但是代谢在肿瘤丝菌相互作用的背景下的作用尚不清楚。此外，尚不清楚自噬如何有助于细胞代谢和肿瘤微环境中的生存。我们假设肿瘤组织中的代谢适应性允许长时间的存活率，以使肿瘤复发，并且辨别基本机制将为癌症治疗提供新的方法。为了检验这一假设，我们计划定义肿瘤和基质细胞代谢，通过自噬来代谢的作用以及代谢应激适应的机理。高密度的生长可诱导成纤维细胞改变新陈代谢，激活自噬，退出细胞周期并输入静止。我们发现，基质成纤维细胞静止的诱导显着改变了基因表达，包括细胞周期再入所需的Notch信号的激活。值得注意的是，葡萄糖消耗和利用率很高，静态成纤维细胞会导致乳酸分泌，从而改变微环境。但是，它如何影响肿瘤发生。类似于成纤维细胞的静态，遭受代谢应激的凋亡缺陷肿瘤细胞会激活自噬，退出细胞周期并进入长时间的休眠状态，当生长条件有利时，它们可以从中重新进入细胞周期。我们发现，肿瘤细胞的休眠大大改变了细胞蛋白质组和基因表达，并用代偿性营养摄取，FOXO和Notch途径激活的证据，以及诱导未经碳源限制引起的乳虫所需的未表征的酵母基因的哺乳动物同源物。这些发现表明，主要代谢重编程伴随着从增殖到休眠到细胞周期再入的过渡。这些静止和休眠之间的惊人相似之处表明，它们受常见的代谢重编程事件的控制，这些事件可能是尚未探索的肿瘤生物学的基本方面。我们建议将代谢网络和代谢的作用定义为细胞从增殖到休眠或静止，再到细胞周期再入的细胞转变，以及这如何改变肿瘤 - 层相互作用。防止肿瘤细胞成功地适应了代谢适应，以使持续休眠和恢复可以提供一种新型的癌症治疗方法。癌细胞获取突变，导致细胞生长也改变了细胞代谢。最近显而易见的是，肿瘤细胞的代谢重编程对于为蛋白质，脂质和核酸的大分子合成提供了支持肿瘤细胞生长所需的核酸，脂质和核酸的基础。重要的是，这些代谢改变将肿瘤细胞与正常细胞区分开，为抗癌药物发现提供了潜在的治疗窗口和新的靶标。 公共卫生相关性：癌细胞获取突变，导致细胞生长也改变了细胞代谢。最近显而易见的是，肿瘤细胞的代谢重编程对于为蛋白质，脂质和核酸的大分子合成提供了支持肿瘤细胞生长所必需的蛋白质，脂质和核酸。重要的是，这些代谢改变将肿瘤细胞与正常细胞区分开，为抗癌药物发现提供了潜在的治疗窗口和新的靶标。

项目成果

LC-MS data processing with MAVEN: a metabolomic analysis and visualization engine.

• DOI: 10.1002/0471250953.bi1411s37
• 发表时间: 2012-03
• 期刊: Current protocols in bioinformatics
• 作者: Clasquin, Michelle F;Melamud, Eugene;Rabinowitz, Joshua D
• 通讯作者: Rabinowitz, Joshua D

Itaconic acid is a mammalian metabolite induced during macrophage activation.

• DOI: 10.1021/ja2070889
• 发表时间: 2011-10-19
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Strelko, Cheryl L.;Lu, Wenyun;Dufort, Fay J.;Seyfried, Thomas N.;Chiles, Thomas C.;Rabinowitz, Joshua D.;Roberts, Mary F.
• 通讯作者: Roberts, Mary F.