Mechanisms of regulated translation control in cancer and its therapeutic implications

癌症中翻译控制的调节机制及其治疗意义

• 批准号: 10436946
• 负责人: Davide Ruggero
• 金额: $ 94.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-06 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436946
• 关键词: Address; Blood; Cells; Development; Diet; Environment; Gene Expression; Gene Expression Regulation; Genetic; Goals; Homeostasis; Human; Link; Malignant Neoplasms; Measures; Messenger RNA; Metabolic; Methods; Mitochondria; Modernization; Molecular; Nutrient; Obesity; Oncogenes; Oncogenic; Pathway interactions; Pharmacogenomics; Pharmacology; Phase; Process; Protein Biosynthesis; Proteome; RNA Cap-Binding Proteins; RNA Splicing; Research; Ribosomes; Series; Signal Transduction; Stream; Therapeutic; Translating; Translations; Tumor Suppressor Genes; Xenograft procedure; cancer cell; cancer genome; cancer initiation; gain of function; genome-wide; in vivo; interest; mouse model; novel; novel therapeutics; patient derived xenograft model; programs; proteostasis; tool; tumor; tumor progression

PROJECT ABSTRACT: Oncogenes and tumor suppressors directly highjack the cell’s translation apparatus to make their own tailored proteome to direct specific steps in cancer development. This is molecularly achieved through translationally regulated nodes of gene expression that can direct cancer initiation and progression. My lab has been at the forefront of this research by generating modern tools and developing the first genetic loss- and gain-of-function mouse models for distinct components of the translation machinery which, in combination with new quantitative measures of the translational landscape of gene regulation, have led to a fundamental change in our understanding regarding the molecular origins of cancer. In this proposal, we will leverage and extend our long-standing interests in translational control in cancer to address three major goals, as follows: 1) What are the synthetic lethal interactions targeting the aberrant translation control program in cancer? Here, we will characterize a series of novel synthetic lethal genetic interactions with the major cap-binding protein eIF4E that we have discovered specific to cancer cells. For example, we will elucidate a surprising genetic interaction between translational control and splicing as well as translation and mitochondrial proteostasis. We will translate these findings to in-vivo mouse models as well as xenografts and patient-derived xenografts to define the importance of such synthetic lethal interactions in human cancers and target them by employing new selective compounds that block eIF4E hyperactivation in human cancers. 2) How is translation control linked to metabolic programs in cancer cells? As nutrient abundance drives anabolic processes, such as protein synthesis, we will determine how translation control influences metabolic homeostasis linked to diet and the cellular environment in cancer. We will assess the functional consequences of genetically and pharmacologically modulating eIF4E activity in cancers associated with obesity and employ unbiased profiling methods to delineate the impact of eIF4E on metabolic signaling that circulates in the blood stream. 3) What are the mechanisms by which oncogenes direct the formation of “cancer ribosomes”? A fundamentally unanswered question is whether the presence of distinct ‘cancer ribosomes’ may drive translation of the cancer genome to direct specific steps in cancer development. We will establish the first systematic, and large-scale characterization of ribosome composition and study its genome-wide impact on gene regulation during distinct phases in Myc-induced tumor development. Importantly, changes in ribosome composition may offer a completely new therapeutic pipeline to selectively inhibit human ribosomes that translate specific, cancer-causing mRNAs.

项目摘要： 癌基因和抑癌基因直接劫持细胞的翻译装置来定制自己的翻译装置 蛋白质组指导癌症发展的特定步骤，这是通过翻译在分子上实现的。 我的实验室一直在研究可以指导癌症发生和进展的基因表达调节节点。 通过生成现代工具并开发第一个基因丧失和功能获得，处于这项研究的最前沿 翻译机器不同组件的小鼠模型，结合新的 基因调控翻译景观的测量，导致了根本性的变化 在这项提案中，我们将利用和扩展我们对癌症分子起源的理解。 人们对癌症转化控制的长期兴趣是为了实现以下三个主要目标：1）什么是 针对癌症中异常翻译控制程序的合成致命相互作用？ 表征了一系列与主要帽结合蛋白 eIF4E 的新型合成致命遗传相互作用 例如，我们将阐明一种令人惊讶的基因相互作用。 我们将在翻译控制和剪接以及翻译和线粒体蛋白质稳态之间进行研究。 将这些发现转化为体内小鼠模型以及异种移植物和患者来源的异种移植物来定义 这种合成致命相互作用在人类癌症中的重要性，并通过采用新的方法来瞄准它们 阻断人类癌症中 eIF4E 过度激活的选择性化合物 2) 翻译控制如何关联。 癌细胞的代谢程序？因为营养丰富会驱动合成代谢过程，例如蛋白质 综合起来，我们将确定翻译控制如何影响与饮食和饮食相关的代谢稳态 我们将评估癌症中的细胞环境的功能后果。 在与肥胖相关的癌症中通过药理学调节 eIF4E 活性并采用公正的分析 描述 eIF4E 对破坏血流的代谢信号的影响的方法 3) 什么。 癌基因指导“癌症核糖体”形成的机制是什么？ 悬而未决的问题是，独特的“癌症核糖体”的存在是否可能驱动癌症核糖体的翻译？ 我们将建立第一个系统的癌症基因组来指导癌症发展的具体步骤。 核糖体组成的大规模表征并研究其对基因调控的全基因组影响 在 Myc 诱导的肿瘤发展的不同阶段，核糖体组成的变化可能会发生。 提供一种全新的治疗途径，选择性抑制翻译特定、 致癌 mRNA。