The contribution of protein translation to tumorigenesis

描述(由申请人提供)：我们已经证明激活蛋白质翻译可以在小鼠模型中驱动肿瘤发生。例如，eIF4E翻译因子可以单独或与c-Myc一起在小鼠中导致肿瘤发展。然而，目前还不清楚增加翻译如何促进肿瘤的发展。我们推测，翻译的激活直接增加了特异性抗凋亡和致癌活性的产生。我们将在我们的提案中使用马赛克小鼠淋巴瘤模型和先进的多聚核糖体图谱技术来验证这一假设。我们之前使用了一个小鼠淋巴瘤模型来展示翻译激活的致癌效应。在目标1中，我们将使用相同的小鼠模型在体内产生淋巴瘤，这些淋巴瘤是由翻译激活驱动的，或者通过翻译无关的机制产生的。为了准确地确定哪些mRNAs被优先翻译，我们将使用多聚核糖体分离和核糖体相关mRNAs的深度测序。接下来，我们将在体外和我们的小鼠模型中测试单个候选基因的肿瘤相关功能。值得注意的是，我们已经确定抗凋亡的MCL1是第一个翻译控制的癌蛋白，并对其功能进行了表征。这些实验现在将作为研究其他候选人的模板(见初步研究和目标2)。在目标3中，我们将使用我们的临床前淋巴瘤模型来测试用小分子(Obtoclax)阻断MCL1的治疗效果。MCL1在一些人类淋巴瘤中高表达，与翻译激活的标志相对应。我们推测，由翻译激活驱动的肿瘤可能表现出对MCL1的需求增加。这项临床前试验是与纪念医院的淋巴瘤服务合作进行的，将直接用于他们对同一化合物的临床试验。总之，这是一项关于翻译调控在肿瘤发生和治疗中的生物学和临床相关性的创新性研究。所有必要的工具都已经到位，例如镶嵌小鼠模型、多聚核糖体分离和454测序技术，我们的临床前试验具有近期临床应用的潜力。此外，我们最近在《基因与发育》上发表的文章表明，成功的研究记录为这一未被研究的肿瘤生物学领域提供了新的见解。 与公共健康相关：癌症是由基因激活的细胞信号引起的，这些信号驱动细胞增殖并反对细胞死亡。最终，这些信号汇聚到执行这些功能的下游效应器，这些效应器通常是蛋白质。我们的研究将描述癌症中蛋白质生产(“翻译”)的变化。我们发现的第一种蛋白质是MCL1，它在淋巴癌(淋巴瘤)中大量产生，使这些肿瘤抵抗细胞死亡。值得注意的是，存在一种可以抑制这种蛋白的药物，我们现在将在小鼠身上测试其对淋巴瘤的效果。我们推测，这种药物应该会增加化疗诱导肿瘤细胞死亡的能力。这项临床前试验是确定该药物是否适合患者的第一步，我们正在与纪念医院临床淋巴瘤科合作进行这些研究，以便我们的结果可以直接反馈到临床试验中。从长远来看，我们希望找到其他像MCL1一样的蛋白质，对于大多数蛋白质来说，药物还没有上市，我们的研究将有助于确定开发新药的优先事项。

DESCRIPTION (provided by applicant): We have shown that activating protein translation can drive tumorigenesis in mouse models. For example, the eIF4E translation factor can cause tumor development in mice alone or with c-Myc. However, it is unclear exactly how increased translation can promote tumor development. We speculate that the activation of translation directly increases the production of specific anti-apoptotic and oncogenic activities. We will test this hypothesis in our proposal using a mosaic mouse lymphoma model and advanced polyribosome profiling techniques. We previously used a mouse lymphoma model to show the oncogenic effect of translational activation. In Aim 1 we will use the same mouse model to generate lymphomas in vivo that are driven by translational activation or arise through a translation-independent mechanism. To identify exactly which mRNAs are preferentially translated, we will then use polyribosome fractionation and deep sequencing of ribosome-associated mRNAs. Next, we will test the tumor relevant functions of individual candidate genes in vitro and in our mouse model. Notably, we have identified the anti-apoptotic Mcl1 as a first translationally controlled oncoprotein, and have characterized its function. These experiments will now serve as a template for the study of additional candidates (see preliminary studies and Aim 2). In Aim 3 we will use our preclinical lymphoma model to test the therapeutic benefit of blocking Mcl1 with small molecule (obatoclax). Mcl1 is highly expressed in some human lymphomas, where it corresponds to markers of translational activation. We speculate that tumors driven by translational activation may show an increased requirement for Mcl1. This preclinical trial is in collaboration with the Lymphoma Service at Memorial Hospital, and will directly feed into their clinical trial on the same compound. Together, this is an innovative study into the biology and clinical relevance of translational regulation in tumorigenesis and therapy. All the necessary tools are in place, e.g. the mosaic mouse model, polyribosome fractionation and 454 sequencing techniques, and our preclinical trial has the potential for near term clinical application. Moreover, our recent publications in Genes & Development indicate a track record of successful studies that have provided new insights in this understudied area of tumor biology. PUBLIC HEALTH RELEVANCE: Cancer is caused by genetic activation cellular signals that drive cell proliferation and oppose cell death. Ultimately, these signals converge on downstream effectors that carry out these functions, these are most often proteins. Our study will characterize changes in protein production ("translation") in cancer. A first protein that we have found to be controlled at the level of protein production is Mcl1, which is highly produced in lymphocyte cancers (lymphoma) and makes these tumors resistant to cell death. Notably, a drug that can inhibit this protein exists and we will now test its effect against lymphomas in mice. We speculate that this drug should increase the ability of chemotherapy to induce cell death in tumors. This preclinical trial is the first step to determine whether the drug is suitable for patients, and we are conducting these studies in collaboration with the clinical lymphoma department of Memorial Hospital, so that our results can directly feed into clinical trials. In the long-term, we expect to find other proteins that behave like Mcl1, for most proteins a drug will not yet be available and our study will help define priorities for developing new drugs.