Mechanisms of regulated translation control in cancer and its therapeutic implications

项目摘要： 癌基因和肿瘤抑制基因直接劫持细胞的翻译装置，为自己量身定做 蛋白质组学指导癌症发展的具体步骤。这是通过翻译分子实现的。 受调控的基因表达节点，可以指导癌症的启动和进展。我的实验室一直在 通过开发现代工具和开发第一个遗传功能丧失和获得，走在了这一研究的前沿 鼠标模型为不同组件的翻译机，结合新的 基因调控的翻译图景的量化措施，已经导致了 我们对癌症分子起源的理解。在这项提案中，我们将利用和扩展我们的 长期以来，人们对癌症的翻译控制感兴趣，以解决以下三个主要目标：1)什么是 针对癌症中异常翻译控制程序的合成致死相互作用？在这里，我们将 表征与主要帽结合蛋白eIF4E的一系列新的合成致死遗传相互作用 我们已经发现了癌细胞的特异性。例如，我们将阐明一种令人惊讶的基因交互作用 翻译控制和剪接以及翻译和线粒体蛋白平衡之间的关系。我们会 将这些发现转化为体内小鼠模型以及异种移植和患者来源的异种移植，以确定 这种人工合成的致命相互作用在人类癌症中的重要性，并通过使用新的 选择性化合物，可阻断人类癌症中eIF4E的过度激活。2)翻译控制是如何链接的 癌细胞的新陈代谢程序？因为营养丰富推动了合成代谢过程，如蛋白质 合成，我们将确定翻译控制如何影响与饮食和 癌症中的细胞环境。我们将评估基因和基因的功能后果 药物调节肥胖相关癌症中eIF4E的活性并采用无偏见的分析 方法描述eIF4E对血流中循环的代谢信号的影响。3)什么 癌基因引导“癌症核糖体”形成的机制是什么？从根本上讲 悬而未决的问题是，不同的“癌症核糖体”的存在是否可能推动翻译 癌症基因组指导癌症发展的具体步骤。我们将建立第一个系统化的、 核糖体组成的大规模表征及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。重要的是，核糖体组成的变化可能 提供一种全新的治疗途径，选择性地抑制人类核糖体翻译特定的， 致癌的核糖核酸。

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.