Decoding the Translational Program Underlying the Oncogenic Stress Response

描述（由申请人提供）：对致癌转化的基本反应是增强的细胞应激（例如氧化、代谢和DNA损伤），这是癌细胞的标志。这些常见的应激表型必须通过应激支持途径被癌细胞耐受。此外，适应压力是癌细胞生存所必需的，因此它们可能依赖于在正常细胞中通常不执行这种重要功能的压力反应途径。因此，针对这些相关的脆弱性进行压力适应显然是至关重要的，并为可能引起癌细胞选择性死亡的合成致命相互作用提供了巨大的机会之窗。尽管癌细胞的应激表型非常重要，但我们对转化细胞中如何维持应激耐受性的遗传基础的理解存在很大差距，从而限制了我们的研究。 设计合理治疗药物的能力。我们的初步研究结果表明，主要的帽结合蛋白eIF4E是一个中央整合的翻译程序的适应癌症 细胞致癌应激。通过产生eIF4E的第一个遗传功能丧失小鼠模型，我们意外地发现eIF4E减少50%对正常发育没有影响，但惊人地限制了致癌转化。利用无偏的全基因组翻译谱分析，我们发现eIF4E选择翻译的特定子集， 参与细胞应激反应途径的mRNA，包括氧化应激。该提案旨在采用多方面的方法来描述eIF4E依赖性控制活性氧在体内非小细胞肺癌的肿瘤发展和维持中的作用，并探索抑制eIF4E与诱导氧化应激的小分子组合的治疗潜力。此外，我们发现eIF4E仅对调节细胞应激反应途径的mRNA的子集具有速率限制作用，这是惊人的，并表明一种新的调节程序促进了癌细胞存活的选择性。我们的目标是确定潜在的分子机制，通过该机制，在选定的mRNA的5'UTR中，一种新的顺式作用调控基序赋予eIF4E敏感性。总的来说，我们的数据表明，这些应激反应途径的eIF4E依赖性控制是致癌转化和肿瘤细胞存活的关键。这些发现为这一提议奠定了基础，该提议旨在为我们理解维持癌细胞适应压力的翻译程序打开一个新的门户，并开发一种新的治疗方案来靶向转化细胞的这种脆弱性。

DESCRIPTION (provided by applicant): A fundamental response to oncogenic transformation is enhanced cellular stress (e.g. oxidative, metabolic, and DNA damage), which is a hallmark of cancer cells. These common stress phenotypes must be tolerated by cancer cells through stress support pathways. Moreover, adaptation to stress is required for cancer cell survival, and consequently they may become dependent on stress response pathways that do not ordinarily perform such a vital function in normal cells. Thus, targeting these associated vulnerabilities to stress adaptation are clearly vital and offer a tremendous window of opportunity for a synthetic lethal interaction that may elicit selective death of cancer cells. Despite the tremendous importance of the stress phenotype of cancer cells, there is a large gap in our understanding of the genetic basis for how stress tolerance is maintained in transformed cells, thereby limiting our ability to design rational therapeutic agents. Our preliminary findings reveal that the major cap-binding protein eIF4E is a central integrator of the translation program for the adaption of cancer cells to oncogenic stress. By generating the first genetic loss-of-function mouse model for eIF4E, we have unexpectedly discovered that a 50% reduction in eIF4E has no effect on normal development, but strikingly is limiting for oncogenic transformation. Utilizing unbiased genome-wide translational profiling, we find that eIF4E selects for the translation of specific subsets of mRNAs involved in cellular stress response pathways, including oxidative stress. This proposal aims to undertake a multifaceted approach to delineate the contribution of eIF4E- dependent control of reactive oxygen species in tumor development and maintenance of non-small cell lung carcinoma in vivo, and explore the therapeutic potential of inhibiting eIF4E in combination with small molecules that induce oxidative stress. Furthermore, our finding that eIF4E is rate limiting for only a subset of mRNAs that regulate cellular stress response pathways is striking, and suggests that a novel regulatory program promotes selectivity for cancer cell survival. We aim to define the underlying molecular mechanisms by which an identified novel cis-acting regulatory motif, in the 5'UTR of select mRNAs, confers eIF4E sensitivity. Collectively, our data demonstrate that eIF4E-dependent control of these stress response pathways is critical for oncogenic transformation and tumor cell survival. These findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the translation program that maintains the adaptation of cancer cells to stress and develop a novel therapeutic regimen to target this vulnerability of transformed cells.