Understanding the role of metabolism in cancer

了解新陈代谢在癌症中的作用

• 批准号: 10240613
• 负责人: MATTHEW G. VANDER HEIDEN
• 金额: $ 89.5万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10240613
• 关键词: Affect; Biochemical Genetics; Biochemistry; Biomass; Cancer Model; Cancer Patient; Cell Culture Techniques; Cell Proliferation; Cells; Cellular Metabolic Process; Diet; Drug resistance; Drug usage; Environment; Environmental Risk Factor; Event; Generations; Genetic; Goals; Laboratories; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Modeling; Normal Cell; Nucleotides; Nutrient; Oxides; Patients; Physiological; Physiology; Production; Proliferating; Regulation; Research; Role; Running; Signal Transduction; Supporting Cell; Technology; Testing; Tissues; Trace Elements Nutrition; Work; cancer cell; cancer genetics; cancer therapy; cancer type; extracellular; genetic approach; glucose metabolism; insight; interest; macromolecule; metabolic abnormality assessment; metabolic phenotype; mouse model; neoplastic cell; novel; programs; tool; tumor; tumor growth; tumor initiation; tumor metabolism; tumor microenvironment; tumor progression

Project Summary Cancer cells have metabolic requirements that differ from most normal, non-proliferating cells. To proliferate, cancer cells must transform available nutrients into the varied array of macromolecules that are needed to build a new cell. Each cancer type is unique and will run a metabolic program that depends on the tissue-of- origin, genetic factors, and the local environment. How specific cancers integrate these cancer cell-intrinsic and extrinsic factors to rewire metabolism and support cancer progression is a major unanswered question. My laboratory's long-term goal is to understand how cancer cell metabolism is adapted to support tumor initiation and progression. The metabolic phenotypes of proliferating cells are typically interpreted with an emphasis on either energy generation or the crosstalk between signaling events and cell metabolism. This has led many to focus on how cancer genetics influences metabolic pathway use. We take a different approach that identifies limiting metabolic processes, considers how these are constrained by the extracellular environment, and defines how metabolic limitations are overcome within a physiological tissue context. Our work has provided insight into understanding how glucose metabolism affects cell proliferation. We found that production of nucleotides and oxidized biomass can be metabolic limitations of cell proliferation and tumor growth, and that both cancer cell-intrinsic and environmental factors determine how cells overcome these limitations. We have developed novel tools to study metabolism in various physiological contexts and uncovered metabolic differences between tumors and cancer cells in culture. We have demonstrated how environmental nutrients and cancer lineage can dictate how metabolism is used to support proliferation and determine sensitivity and resistance to drugs used in patients. Our work has charted new research directions for the field and contributed new ideas to exploit altered metabolism to help cancer patients. Using mass spectrometry to trace nutrient fate in cancer models, my laboratory generates hypotheses for how different cancers use metabolism to support cell proliferation and tumor growth. We test these hypotheses using a variety of biochemical and genetic approaches to define how nutrient availability, metabolic pathway regulation, and tissue context constrain how cells use available materials to proliferate. Our current interests include identifying which metabolic processes create bottlenecks for cell proliferation, determining how metabolism is different in different cancers, examining in detail the influence of tissue type, tumor genetics, and tumor microenvironment, and understanding how diet and whole body metabolism influence tumor metabolism and cancer progression. We aim to advance understanding of metabolic pathway biochemistry, its relationship to cancer and mammalian physiology, and identify how best to target metabolism for therapy.

项目摘要 癌细胞的新陈代谢需求与大多数正常的非增殖细胞不同。为了扩散， 癌细胞必须将可用的营养物质转化为各种大分子，这些大分子是 建造一个新的牢房。每种癌症类型都是独一无二的，并将运行依赖于组织的新陈代谢程序。 起源、遗传因素和当地环境。特定的癌症如何整合这些癌细胞--固有的和 改变新陈代谢和支持癌症进展的外在因素是一个主要的未解答的问题。 我的实验室的长期目标是了解癌细胞的新陈代谢如何适应以支持肿瘤 开始和进展。增殖细胞的代谢表型通常用一种 强调能量产生或信号事件与细胞新陈代谢之间的串扰。这有 导致许多人关注癌症遗传学如何影响代谢途径的使用。我们采取了不同的方法 确定限制新陈代谢的过程，考虑这些过程如何受到细胞外的限制 并定义了如何在生理组织环境中克服代谢限制。 我们的工作为理解葡萄糖代谢如何影响细胞增殖提供了洞察力。我们发现 核苷酸和氧化生物量的产生可能是细胞增殖和肿瘤的代谢限制 癌细胞的内在因素和环境因素都决定了细胞如何克服这些 限制。我们已经开发了新的工具来研究各种生理环境中的新陈代谢和 发现了肿瘤和癌细胞在培养过程中的代谢差异。我们已经演示了如何 环境营养素和癌症谱系可以决定新陈代谢如何用于支持增殖和 确定患者使用的药物的敏感性和耐药性。我们的工作开辟了新的研究方向 为这一领域做出了贡献，并为利用改变的新陈代谢来帮助癌症患者贡献了新的想法。 使用质谱仪追踪癌症模型中的营养命运，我的实验室产生了关于如何 不同的癌症利用新陈代谢来支持细胞增殖和肿瘤生长。我们检验了这些假说 使用各种生化和遗传方法来定义养分的有效性、代谢途径 调控和组织环境限制了细胞如何使用可用材料进行增殖。我们目前的利益 包括确定哪些代谢过程对细胞增殖造成瓶颈，确定如何 代谢在不同的癌症中是不同的，详细检查组织类型、肿瘤遗传学和 肿瘤微环境，了解饮食和全身代谢如何影响肿瘤代谢 以及癌症的进展。我们的目标是促进对代谢途径生物化学及其关系的理解 癌症和哺乳动物生理学，并确定如何最好地针对新陈代谢进行治疗。