Investigating the Role of Metabolic Reprogramming in Cancer Cell Death Sensitivity

研究代谢重编程在癌细胞死亡敏感性中的作用

• 批准号: 9652179
• 负责人: Amy Tarangelo
• 金额: $ 3.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9652179
• 关键词: Address; Affect; Amino Acids; Antioxidants; Attention; Biochemical; Biochemical Pathway; Biological Assay; Biological Models; CDKN1A gene; Cancer Biology; Cancer Cell Growth; Cancer Model; Cell Culture Techniques; Cell Death; Cell model; Cells; Cellular Metabolic Process; Cellular Stress; Chemicals; Complex; Consumption; Cysteine; Dependence; Development; Doctor of Philosophy; Drug Tolerance; Environment; Enzymes; Excretory function; Exposure to; Folic Acid; Genes; Genetic; Genetic Transcription; Glutathione; Glutathione Disulfide; Glutathione Metabolism Pathway; Goals; Growth; Head; Human; In Vitro; Iron; Laboratory Research; Laboratory Study; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic stress; Metabolism; Methotrexate; Modeling; Mus; Mutation; Natural regeneration; Oncogenes; Oncogenic; Pathway interactions; Phenotype; Physiological; Positioning Attribute; Predisposition; Protein p53; Reactive Oxygen Species; Reduced Glutathione; Research; Research Personnel; Research Project Grants; Resistance; Role; Scientist; Secure; Serum; System; TP53 gene; Technical Expertise; Testing; Therapeutic; Training; Tumor Suppressor Genes; Work; Xenograft Model; anticancer research; cancer cell; cancer survival; cancer therapy; chemotherapy; deprivation; design; drug sensitivity; experience; experimental study; fibrosarcoma; improved; in vivo; lipid metabolism; metabolic abnormality assessment; neoplastic cell; novel; novel therapeutic intervention; oxidation; post-doctoral training; pre-doctoral; skills; therapeutic candidate; therapeutic target; therapy development; tissue culture; tool; tumor; tumor metabolism; tumor progression

ABSTRACT Alterations in the metabolism of cancer cells can directly promote growth and survival and create metabolic dependencies. Targeting these metabolic dependencies is an attractive strategy for designing novel anti-cancer therapies. The development of these treatments is hindered by a major gap in our understanding of how changes in cancer cell metabolism, and in particular lipid metabolism, alter sensitivity to cell death induced by chemotherapy. My goal is to mechanistically define the links between cancer-associated mutations, metabolic lipid reprogramming, and sensitivity to cell death. F99 Training: During my dissertation research, I investigated the genetic and metabolic factors mediating cancer cell sensitivity to ferroptosis, a form of non-apoptotic cell death that occurs due to metabolic stress. Ferroptosis occurs when cells are deprived of the essential intracellular antioxidant, glutathione, leading to the toxic, iron-dependent accumulation of lipid reactive oxygen species (ROS). I discovered that the canonical tumor suppressor p53 and its downstream transcriptional target CDKN1A (encoding p21), suppress ferroptosis by reprogramming glutathione metabolism and decreasing the accumulation of lipid ROS. From this work it remains unclear how the p53-p21 pathway reprograms glutathione metabolism. I hypothesize that the p53-p21 pathway promotes the regeneration of reduced glutathione from oxidized glutathione to block lipid ROS accumulation. I will test this hypothesis in vivo and in vitro using genetic and chemical tools, metabolic tracing analysis, and mouse cancer models. This training will allow me to develop the skills and experience necessary to secure and succeed in a postdoctoral position at a top laboratory studying cancer metabolism. K00 Training: Alterations in lipid metabolism are common in cancer and may directly facilitate growth and survival. How changes in lipid metabolism impact cancer cell sensitivity to chemotherapy- induced cell death is not well understood. A major challenge in answering this question is that lipid metabolism is highly responsive to environmental conditions, and in vitro tissue culture systems poorly recapitulate the specific lipid metabolic environment experienced by cancer cells exposed to human serum. During my postdoctoral training, I will address this critical problem by developing new tools to more closely mimic the in vivo lipid metabolic environment in cell culture. Using these tools, I will determine how reprogramming of lipid metabolism alters cancer cell sensitivity to chemotherapy-induced cell death using large-scale genetic and chemical approaches. The training of the K00 will enable me to gain the technical and professional skills necessary to achieve my long-term goal of becoming an independent cancer investigator.

摘要 癌细胞代谢的改变可以直接促进生长和存活，并产生代谢性肿瘤。 个依赖项靶向这些代谢依赖性是设计新型抗癌药物的有吸引力的策略 治疗这些治疗方法的发展受到阻碍，因为我们对如何改变的理解存在重大差距。 在癌细胞代谢，特别是脂质代谢中，改变了对 化疗我的目标是从机制上定义癌症相关突变、代谢异常和癌症之间的联系。 脂质重编程和对细胞死亡的敏感性。F99培训：在我的论文研究期间，我调查了 介导癌细胞对铁凋亡（一种非凋亡细胞形式）敏感性的遗传和代谢因子 由于代谢压力而导致的死亡。当细胞被剥夺了必需的细胞内营养时， 抗氧化剂谷胱甘肽，导致脂质活性氧簇的毒性、铁依赖性积累 （ROS）。我发现典型的肿瘤抑制基因p53及其下游转录靶点CDKN 1A （编码p21），通过重新编程谷胱甘肽代谢和减少铁蛋白的合成来抑制铁蛋白缺乏症。 脂质ROS的积累。从这项工作中，仍然不清楚p53-p21途径如何重新编程谷胱甘肽 新陈代谢.我推测p53-p21通路促进了还原型谷胱甘肽的再生， 氧化谷胱甘肽以阻断脂质ROS积累。我将在体内和体外使用遗传学方法来检验这一假设。 化学工具、代谢追踪分析和小鼠癌症模型。这次训练会让我 在顶级实验室学习博士后职位并取得成功所需的技能和经验 癌症代谢K 00培训：脂质代谢的改变在癌症中很常见， 促进生长和生存。脂质代谢的变化如何影响癌细胞对化疗的敏感性- 诱导的细胞死亡还不太清楚。回答这个问题的一个主要挑战是脂质代谢 是高度响应于环境条件，并在体外组织培养系统很难概括的 暴露于人血清的癌细胞所经历的特定脂质代谢环境。在我 在博士后培训中，我将通过开发新的工具来更紧密地模拟体内 细胞培养中的脂质代谢环境。利用这些工具，我将确定脂质的重编程 代谢改变癌细胞对化疗诱导的细胞死亡的敏感性， 化学方法。K 00的培训将使我获得技术和专业技能 这是我实现成为一名独立癌症研究者的长期目标所必需的。