Breaking the paradigm: RhoA as a tumor suppressor in cancer

摘要/项目摘要 Ras同源蛋白(Rho)是RAS小分子GTP酶超家族的一个重要分支。我的 研究的重点是RhoA。由于RhoA与RAS在结构和生化上有显著的相同之处 癌蛋白，早期研究表明RhoA也可能作为癌基因发挥作用并驱动 癌症生长。由于RhoA调节肌动蛋白细胞骨架、细胞迁移和运动以及细胞周期 进展，RhoA功能异常确实会影响癌细胞的生物学，这似乎是合乎逻辑的。 支持RhoA的癌基因作用，早期研究设计了基于RhoA的激活突变体 在RAS中发现与癌症相关的突变。这些在啮齿动物成纤维细胞模型中的研究观察到 支持突变体RhoA在癌症中的作用。因此，令人失望的是，当早期癌症基因组 测序研究未能在最常见的癌症类型中发现RHOA突变。这一点在 2014年，T细胞淋巴瘤和胃癌的测序研究发现，在 罗亚。然而，发现的突变是意想不到的，这表明RhoA的损失而不是获得 功能是导致这些癌症类型生长的原因。我的研究将解决这个显而易见的问题 该领域的悖论：RhoA功能的增强或丧失是导致癌症的重要因素？我建议 完成三个癌症相关RhoA突变体的综合生化和细胞评估 目的是(1)确定RhoA癌相关突变引起的生化缺陷；(2)评估 这些RhoA突变体的细胞活动以评估功能的获得或丧失；以及(3)确定不同的RhoA 突变可以驱动癌症相关的生长表型。总而言之，我的研究将提供更好的 从机制上理解异常的RhoA功能可能如何推动癌症生长，这是 指导开发治疗RHOA突变癌症的药理学方法。 此外，这些研究将使我接触到各种各样的技术和工具，并将增强 我作为一名癌症研究人员的发展。

Abstract/Project Summary The Ras homologous (Rho) proteins comprise a major branch of the Ras superfamily of small GTPases. My studies are focused on RhoA. Since RhoA shares significant structural and biochemical identities with the Ras oncoproteins, early studies addressed the possibility that RhoA may also function as an oncogene and drive cancer growth. Since RhoA regulates the actin cytoskeleton, cell migration and motility, and cell cycle progression, it seems logical that aberrant RhoA function can indeed impact the biology of cancer cells. Supporting an oncogene role for RhoA, early studies designed activated mutants of RhoA based on the cancer-associated mutants found in Ras. These studies in rodent fibroblast models made observations that supported mutant RhoA function in cancer. Therefore, it was disappointing when early cancer genome sequencing studies failed to identify RHOA mutations in the most common cancer types. This changed in 2014 when sequencing studies of T cell lymphomas and gastric cancers found recurrent missense mutations in RHOA. However, the mutations found were unexpected and suggested that loss rather than gain of RhoA function was responsible for driving the growth of these cancer types. My studies will address this apparent paradox in the field: is it a gain or loss of function in RhoA that is important to drive cancer? I propose comprehensive biochemical and cellular evaluation of the cancer-associated RhoA mutants to complete three aims to (1) determine the biochemical defect caused by cancer-associated mutations in RhoA; (2) evaluate the cellular activities of these RhoA mutants to assess gain or loss of function; and (3) determine if different RhoA mutants can drive cancer-associated growth phenotypes. In summary, my studies will provide a better mechanistic understanding of how aberrant RhoA function may drive cancer growth, an important first step to guide the development of pharmacologic approaches for the treatment of RHOA-mutant cancers. Furthermore, these studies will expose me to a wide variety of techniques and instruments and will enhance my development as a cancer researcher.