Oncogenic Ras-induced macropinocytosis: A new paradigm for metabolic adaptation

致癌 Ras 诱导的巨胞饮作用：代谢适应的新范例

• 批准号: 9348606
• 负责人: DAFNA BAR-SAGI
• 金额: $ 99.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348606
• 关键词: Address; Amino Acids; Cells; Coupled; Extracellular Protein; Goals; Intervention; Laboratories; Liquid substance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mutation; Nutrient; Oncogenic; Phase; Plant Roots; Positioning Attribute; Process; Research; Resistance; Testing; Therapeutic; Translating; Work; base; career; effective therapy; insight; mutant; neoplastic cell; novel; programs; targeted treatment; therapeutic target; tumor; uptake

Tumors harboring oncogenic Ras mutations are notoriously resistant to existing targeted therapies. This grave reality coupled with the fact that Ras mutations are prevalent in some of the deadliest cancers underscore the urgent need to identify new targeting strategies that can be translated to effective therapies for Ras-driven tumors. The overarching goal of this research program is to address this need by capitalizing on the emerging paradigm that the metabolic rewiring of Ras tumor cells constitutes a core vulnerability that can be exploited therapeutically. Specifically, we will pursue a novel nutrient delivery mechanism that was recently elucidated in my laboratory and is rooted in a discovery I made earlier in my career that oncogenic Ras stimulates a fluid-phase endocytic process known as macropinocytosis (MP). We recently discovered that this process is exploited by mutant Ras cells to internalize extracellular protein and deliver it to where it is degraded to generate free amino acids that can fuel metabolic pathways. Our studies to date strongly indicate that understanding the molecular underpinnings of this process and defining its pathophysiological consequences hold promise for defining new intervention approaches for mutant Ras tumors. We propose to rigorously test this idea by pursuing three broad questions: 1) How does oncogenic Ras regulate MP? 2) What are the functional consequences of oncogenic-Ras mediated MP?, and 3) Can MP be exploited as a therapeutic target? We are uniquely positioned to address these questions owing to the progress we have made thus far and our access to relevant expertise. We anticipate that this research program will yield new insights into Ras-dependent oncogenic mechanisms of translational relevance. .

具有致癌RAS突变的肿瘤众所周知对现有靶向 疗法。这种严重的现实加上以下事实：RAS突变在某些中普遍存在 最致命的癌症强调了可以识别可以翻译的新目标策略的迫切需求 为RAS驱动肿瘤的有效疗法。该研究计划的总体目标是 通过利用新兴范式来满足这种需求 细胞构成可以通过治疗方法利用的核心脆弱性。具体来说，我们将追求 最近在我的实验室中阐明的新型营养递送机制，并植根于 我在职业生涯早些时候做出的发现，致癌性RA刺激了流体相位的内吞过程 称为大型细胞增多症（MP）。我们最近发现该过程被突变的RAS利用 细胞内化细胞外蛋白并将其递送到降解以产生游离氨基的位置 可以燃烧代谢途径的酸。迄今为止，我们的研究强烈表明 该过程的分子基础并定义其病理生理后果 定义突变RAS肿瘤的新干预方法的承诺。我们建议严格 通过提出三个广泛的问题来测试这个想法：1）致癌RAS如何调节MP？ 2）是什么 致癌-ras介导的MP的功能后果和3）MP可以被用作一个 治疗目标？由于我们的进步，我们有独特的位置来解决这些问题 到目前为止，我们已经获得了相关专业知识。我们预计该研究计划将 对转化相关性的RAS依赖性致癌机制产生新的见解。 。