Breaking the paradigm: RhoA as a tumor suppressor in cancer

打破范式：RhoA 作为癌症的肿瘤抑制因子

• 批准号: 9328936
• 负责人: Devon R Blake
• 金额: $ 3.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328936
• 关键词: Actins; Address; Affinity; Automobile Driving; Bass; Biochemical; Biological; Biological Assay; Biological Process; Biology; Cancer Biology; Cancer Etiology; Cancer cell line; Cell Cycle Progression; Cell Surface Receptors; Cell model; Cells; Cellular biology; Collaborations; Cytoskeleton; Defect; Development; Dimensions; Disseminated Malignant Neoplasm; Dominant-Negative Mutation; Epithelial Cells; Evaluation; Exhibits; Fibroblasts; Focal Adhesions; GTPase-Activating Proteins; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homologous Protein; Human; In Vitro; Lead; Location; Malignant Neoplasms; Mediating; Missense Mutation; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutation; Neoplasm Metastasis; Normal Cell; Nucleotides; Oncogenes; Oncoproteins; Organoids; Pharmacology; Phenotype; Play; Property; Proteins; RHOA gene; Recombinants; Recurrence; Regulation; Research Design; Research Personnel; Research Training; Rodent; Role; Signal Pathway; Signal Transduction; Stomach; Stress Fibers; System; T-Cell Lymphoma; Techniques; Tumor Suppressor Proteins; United States National Institutes of Health; base; cancer genome; cancer type; cell motility; gain of function; gain of function mutation; genome sequencing; in vivo; instrument; knock-down; loss of function; malignant stomach neoplasm; mutant; ras Oncogene; receptor-mediated signaling; small hairpin RNA; tumor growth

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.

摘要/项目摘要 Ras同源（Rho）蛋白包含小GTP酶的Ras超家族的主要分支。我 研究集中在RhoA上。由于RhoA与Ras具有重要的结构和生化特性， 癌蛋白，早期的研究提出了RhoA也可能作为一种癌基因发挥作用，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， 随着癌症的进展，异常的RhoA功能确实可以影响癌细胞的生物学似乎是合乎逻辑的。 支持RhoA的致癌基因作用，早期的研究设计了RhoA的激活突变体，其基础是 Ras中发现的癌症相关突变体。这些在啮齿动物成纤维细胞模型中的研究观察到， 支持突变型RhoA在癌症中的功能。因此，当早期癌症基因组 测序研究未能鉴定最常见癌症类型中的RHOA突变。这一变化在 2014年，T细胞淋巴瘤和胃癌的测序研究发现， RHOA。然而，发现的突变是出乎意料的，表明RhoA的丢失而不是获得， 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明显的 该领域的悖论：RhoA功能的获得或丧失对驱动癌症很重要吗？我提议 对癌症相关RhoA突变体进行全面的生化和细胞评估，以完成三项 目的是（1）确定RhoA中癌症相关突变引起的生化缺陷;（2）评估 这些RhoA突变体的细胞活性，以评估功能的获得或丧失;以及（3）确定不同的RhoA 突变体可以驱动癌症相关的生长表型。总之，我的研究将提供一个更好的 对异常RhoA功能如何驱动癌症生长的机制的理解， 指导开发治疗RHOA突变型癌症的药理学方法。 此外，这些研究将使我接触到各种各样的技术和工具，并将提高 我作为癌症研究者的发展