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. .

众所周知，携带致癌 Ras 突变的肿瘤对现有的靶向药物具有抵抗力。 疗法。这一严峻的现实加上 Ras 突变在某些物种中普遍存在的事实 最致命的癌症强调迫切需要确定可转化的新靶向策略 Ras 驱动的肿瘤的有效疗法。该研究计划的总体目标是 通过利用 Ras 肿瘤代谢重连这一新兴范式来满足这一需求 细胞构成了可用于治疗的核心脆弱性。具体来说，我们将追求 我的实验室最近阐明了一种新颖的营养输送机制，其根源在于 我在职业生涯早期发现致癌 Ras 会刺激液相内吞过程 称为巨胞饮作用（MP）。我们最近发现这个过程被突变型 Ras 利用 细胞内化细胞外蛋白质并将其运送到降解处产生游离氨基酸 可以促进代谢途径的酸。我们迄今为止的研究强烈表明，了解 这一过程的分子基础并定义其病理生理学后果 有望为突变 Ras 肿瘤定义新的干预方法。我们建议严格 通过提出三个广泛的问题来检验这个想法：1）致癌 Ras 如何调节 MP？ 2）什么是 致癌 Ras 介导的 MP 的功能后果？以及 3) MP 能否被利用作为 治疗目标？由于我们所取得的进展，我们处于解决这些问题的独特地位 到目前为止，我们已经获得了相关的专业知识。我们预计该研究计划将 对 Ras 依赖性致癌机制的翻译相关性产生新的见解。 。