Cancer Hijacks Enzyme Substrate Mutations to Facilitate Tumorigenesis

项目摘要 生命事件的遗传信息编码，包括疾病相关的变化和癌症治疗的提示。 一项艰巨的任务是破译遗传信息。一种常见的方法是调查基因变化 癌症的发生与肿瘤的发生有关。人们一直致力于确定关键基因 扩增/缺失/融合事件和阐明热突变相关的酶变化和相互作用组 改变。然而，酶的突变只占整个突变格局的一小部分，而且 大多数非酶突变的意义尚不清楚。为此，我们开发了一种算法 为了挖掘针对未被研究的非酶突变的关键酶底物基序的获得或丢失 TCGA数据库，通过该数据库可以改变关键酶的功能。作为一项原则证明研究，使用这个 方法我们已经在癌症中发现了1792个突变，其中一个新的AGC激酶基序丢失了。这些 突变在结肠癌和食道癌中更加丰富，更有可能影响细胞信号通路。 更重要的是，我们验证了一次HIT，BUD13，在突变时可以绕过一次AGC的磷酸化 激酶GRK6，这些缺乏磷酸化的癌性BUD13突变通过它获得致癌活性 通过上调mTORC1信号来促进结肠癌的生长。在这份提案中，我们将系统地 确定所有特征酶基序的第一个突变环境，并进一步验证重要的HITS 一条我们有专业知识的试验性管道。我们还将研究相关的新治疗方向 野生型和突变型BUD13在体外细胞培养模型和体内结肠癌中的表达 临床前动物模型。我们希望我们的研究将为癌症劫持突变提供新的见解 促进肿瘤发生，具有患者分层和癌症治疗的潜力。

PROJECT ABSTRACT Genetic information codes for life events including disease associated changes and hints for cancer treatments. A daunting task is to decode genetic information. A common approach is to investigate whether genetic changes in cancer are associated with tumorigenesis. Efforts have been devoted to identifying key gene amplification/deletion/fusion events and elucidating hot mutation-associated enzymatic changes and interactome changes. However, mutations on enzymes only account for a small portion of total mutational landscape and meanings of the majority of non-enzyme mutations remain unclear. To this end, we have developed an algorithm to mine the gain or loss of key enzyme substrate motifs targeting the understudied non-enzyme mutations from TCGA database, through which key enzyme functions can be altered. As a proof-of-principle study, using this approach we have identified 1,792 mutations in cancer that a new motif for the AGC kinases is lost. These mutations are more enriched in colon and esophageal carcinoma to more likely affect cellular signaling pathways. More importantly, we validated that one hit, BUD13, upon mutation can bypass its phosphorylation by one AGC kinase GRK6, through which these cancerous BUD13 mutations deficient in phosphorylation gain oncogenicity to promote colon cancer growth through elevating the mTORC1 signaling. In this proposal, we will systematically identify the first mutational landscape for all characterized enzyme motifs and further validate important hits using an experimental pipeline that we have expertise on. We will also examine new therapeutic directions associated with both WT- and mutant-BUD13 expressing colon cancer in both in vitro cell culture models and in vivo preclinical animal models. We hope that our study will provide novel insights for mutations cancer hijacks to promote tumorigenesis with the potential for patient stratification and cancer treatment.