Dissecting the role of mitochondrial glutathione homeostasis in cancer

剖析线粒体谷胱甘肽稳态在癌症中的作用

• 批准号: 10743695
• 负责人: Yuyang Liu
• 金额: $ 4.92万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743695
• 关键词: Animal Model; Antioxidants; Binding; Biochemical; Biological Process; Biomass; Breast Cancer cell line; Breast cancer metastasis; CRISPR screen; Cancer Model; Cancerous; Cell Survival; Cells; Cytosol; Engineering; Ensure; Enzymes; Epitopes; Eukaryotic Cell; Feedback; Gene Expression; Glutathione; Glutathione Metabolism Pathway; Growth; Heterogeneity; Homeostasis; Immune system; Immunoprecipitation; Immunotherapy; Iron; Knock-out; Label; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Messenger RNA; Metabolic; Metabolic stress; Metabolism; Metastatic breast cancer; Mitochondria; Modeling; Mus; Neoplasm Metastasis; Nutrient; Organelles; Oxidation-Reduction; Paint; Pathologic; Pathway interactions; Peptide Hydrolases; Phase; Physiological; Play; Post-Translational Regulation; Process; Proteins; Proteolysis; Publishing; Radioactive; Reduced Glutathione; Refuse Disposal; Regulation; Reporter; Resolution; Role; Stress; Sulfur; Testing; Tumor stage; Work; activity-based protein profiling; cancer cell; cell type; detection of nutrient; insight; mutant; neoplastic cell; novel; novel therapeutic intervention; posttranscriptional; prevent; prototype; response; single cell sequencing; single-cell RNA sequencing; tool; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; uptake

Project Summary All eukaryotic cells, whether normal or cancerous, require the ability to sense changes in nutrients levels, ensuring their efficient use for survival and growth. Nutrient sensing mechanisms enable cells to rapidly adapt to environmental perturbation, a feature particularly essential for cancer cells to overcome diverse metabolic stresses along the metastatic cascade. Although many nutrient sensing mechanisms have been described, how metabolites are sensed in subcellular compartments remains a major open question. This question is particularly relevant for redox-active molecules such as NAD and glutathione, which display remarkably heterogenous distribution across subcellular compartments and have been shown to play key roles in cancer metastasis. Recent breakthroughs in deorphanizing mitochondrial metabolite transporters provided unprecedented opportunity to probe the dynamics and sensing mechanism of these metabolites at subcellular precision. In a recently published study, SLC25A39 has been identified as a key transporter for mitochondrial glutathione, a major antioxidant molecule implicated in cancer progression and metastasis. Remarkably, evidence suggests that SLC25A39 undergoes feedback regulation by mitochondrial glutathione and may be required for efficient metastatic colonization, implicating it in an adaptive mechanism for cancers to overcome metabolic stress during metastasis. This proposal seeks a deeper understanding of the implication of organellar glutathione metabolism in cancer. The Aim 1 of this proposal seeks to understand the role of mitochondrial glutathione homeostasis in tumor progression and metastasis and decipher the mechanism of its regulation. The Aim 2 of this proposal seeks to develop novel genetically encoded, single-cell RNAseq-compatible reporters for profiling intercellular heterogeneity in mitochondrial glutathione in tumors. Using a combination of biochemical analysis, unbiased CRISPR screens and novel animal models, this proposal aims to paint a multilayered picture of the dynamics, regulatory mechanisms and functional contribution of mitochondrial glutathione homeostasis in tumor progression and metastasis. Completion of the proposed studies will deepen our understanding on the role of compartmentalized metabolite pools in metabolic rewiring of cancers and shed light on novel therapeutic strategies to target metastasis.

项目概要 所有真核细胞，无论是正常细胞还是癌细胞，都需要能够感知营养水平的变化， 确保其有效利用以维持生存和发展。营养感应机制使细胞能够快速适应 环境扰动，这是癌细胞克服多种代谢特别重要的特征 沿转移级联的应力。尽管已经描述了许多营养传感机制，但如何 在亚细胞区室中感知代谢物仍然是一个主要的悬而未决的问题。这个问题特别 与 NAD 和谷胱甘肽等氧化还原活性分子相关，这些分子表现出明显的异质性 跨亚细胞区室的分布，并已被证明在癌症转移中发挥关键作用。 最近在线粒体代谢物转运蛋白去孤儿化方面取得的突破提供了前所未有的 有机会以亚细胞精度探索这些代谢物的动力学和传感机制。在一个 最近发表的研究表明，SLC25A39 已被确定为线粒体谷胱甘肽的关键转运蛋白，线粒体谷胱甘肽是一种线粒体谷胱甘肽的关键转运蛋白。 与癌症进展和转移有关的主要抗氧化剂分子。值得注意的是，有证据表明 SLC25A39 接受线粒体谷胱甘肽的反馈调节，并且可能是有效 转移定植，表明它与癌症克服代谢应激的适应性机制有关 转移。 该提案寻求更深入地了解细胞器谷胱甘肽代谢在癌症中的影响。 该提案的目标 1 旨在了解线粒体谷胱甘肽稳态在肿瘤中的作用 进展和转移并破译其调节机制。该提案的目标 2 旨在 开发新型遗传编码、单细胞 RNAseq 兼容的报告基因，用于分析细胞间质 肿瘤中线粒体谷胱甘肽的异质性。采用生化分析相结合，公正 CRISPR 筛选和新颖的动物模型，该提案旨在描绘动态的多层图景， 线粒体谷胱甘肽稳态在肿瘤中的调节机制和功能贡献 进展和转移。完成拟议的研究将加深我们对 癌症代谢重连中的区室化代谢物池并揭示新的治疗方法 针对转移的策略。