The Role of RHOA in Diffuse Gastric Cancer

RHOA 在弥漫性胃癌中的作用

• 批准号: 10391832
• 负责人: Adam Joel Bass
• 金额: $ 81.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391832
• 关键词: Automobile Driving; Bass; Belief; Biochemical; Biological Assay; Biological Models; CDH1 gene; Cancer Model; Cancer cell line; Cell secretion; Cells; Cellular biology; Cessation of life; Characteristics; Chronic; Collaborations; Critical Pathways; DNA Sequence Alteration; Data; Data Set; Development; Diffuse gastric cancer; Disease; Disseminated Malignant Neoplasm; Engineering; Epithelial; Foundations; Functional disorder; Gastric Glands; Gastric ulcer; Gastritis; Genetic; Genomics; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Hydrolysis; In Vitro; Inflammation; Injury; Knockout Mice; Malignant Neoplasms; Mediating; Mediator of activation protein; Missense Mutation; Monomeric GTP-Binding Proteins; Mus; Mutation; Natural regeneration; Nature; Neoplasm Metastasis; Oncogenic; Organoids; Pathogenesis; Pathologic; Pathway interactions; Pattern; Phenotype; Property; Protein-Serine-Threonine Kinases; RHOA gene; ROR1 gene; Recurrence; Regulation; Research; Research Personnel; Role; Signal Transduction; Somatic Mutation; Stomach; Structural Biochemistry; Study models; System; Testing; The Cancer Genome Atlas; Tumor Suppressor Proteins; Uncertainty; cancer cell; cancer initiation; carcinogenesis; cohesion; data resource; effective therapy; fusion gene; gain of function; gastric cancer cell; gastric corpus; genomic aberrations; in vivo; inhibitor/antagonist; injury and repair; insight; malignant stomach neoplasm; mouse model; mutant; new therapeutic target; novel; prevent; programs; receptor; repaired; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; stem cell niche; stem cell population; stem cell self renewal; stem cells; therapeutic target; tumor progression

PROJECT SUMMARY This project focuses upon Diffuse Gastric Cancer (DGC), a frequently lethal cancer, marked by its characteristic growth patterns with lack of cellular cohesion, highly invasive spread and marked propensity for metastasis. This proposal builds upon new progress in the study of DGC, bringing together a collaborative team of investigators with provocative new findings regarding the role of RHOA in the pathogenesis of this disease and several newly developed mouse model systems. These data and resources bring new opportunities to substantively advance the study of these deadly and understudied cancers. A first set of data underlying this application followed our recent identification of a novel stem cell population in gastric glands marked by Mist1 expression (Yokoyama et al, Cancer Cell 2015). These cells were demonstrated to give rise to DGC following engineered loss of tumor suppressor Cdh1. However, development of DGC required the secretion of Wnt5a by cells in the stem cell niche, with Wnt5a acting by activating GTPase RhoA in the Cdh1- null gastric cells. In parallel, we made a set of novel genomic discoveries, finding that ~20- 30% of DGCs harbor genomic aberrations impacting RHOA, either highly recurrent missense mutations of RHOA or a recurrent fusion gene including ARHGAP26, a RHOA regulator (TCGA, Nature, 2014). In this context, delineating the functions of RhoA in DGC pathogenesis, spanning both the role of Wild-type RHOA following Cdh1 loss and the oncogenic functions of RHOA mutations, emerge as critical paths towards the identification of therapeutic targets and understanding of basic pathophysiology of DGC formation. In our first Aim, we evaluate activation of wild-type RHOA in normal gastric corpus stem cells, and in early progression of Cdh1- deficient diffuse gastric cancer. We propose to test our hypothesis that RHOA is a mediator of Wnt5a effects upon corpus stem cells, especially following Cdh1 loss. These results will have immediate relevance to the definition of mechanisms of DGC initiation, clearly informing efforts to prevent and treat these deadly cancers. Our second aim evaluates RHOA somatic mutations in the initiation and progression of diffuse gastric cancer. In this aim we further characterize the biochemical and phenotypic effects of highly recurrent missense mutations of the RHOA GTPase identified in DGC. We will also functionally validate which RHOA effectors are essential for oncogenic activity of these mutants in both in vitro and in vivo systems, including our novel DGC mouse model driven by Cdh1 loss and RhoA mutation. Through these studies we hope to determine mechanisms of RHOA mediated transformation and identify specific pathways that are critical to the pathogenesis of DGC, findings with immediate potential relevance to the development of new therapeutic targets.

项目总结 这个项目的重点是弥漫性胃癌(DGC)，一种经常致命的癌症， 由于其特有的生长模式缺乏细胞凝聚力，高度侵袭性传播和 有明显的转移倾向。这项建议建立在DGC研究的新进展的基础上， 将一个合作的调查团队聚集在一起，提出关于 RHOA在本病发病机制中的作用及几种新发展的小鼠模型 系统。这些数据和资源带来了新的机遇，实质性地推进了 这些致命且未被充分研究的癌症。此应用程序背后的第一组数据遵循我们的 以Mist1表达为标记的胃腺中一种新的干细胞群的最新鉴定 (横山等人，《癌症细胞2015》)。这些细胞被证实可以在下列情况下产生DGC 肿瘤抑制基因cdh1的工程性缺失。然而，DGC的发展需要分泌 干细胞巢中的细胞对Wnt5a的作用，Wnt5a通过激活GTP酶RhoA在 CDH1缺失的胃细胞。与此同时，我们做出了一系列新的基因组发现，发现~20- 30%的DGC存在影响RHOA的基因组异常，要么是高度重复的错义 RHOA或包括ARHGAP26、RHOA调节因子(TCGA， 《自然》，2014)。在此背景下，描绘了RhoA在DGC发病机制中的功能，跨越 野生型RHOA在CDH1缺失后的作用及其致癌功能 突变，成为识别治疗靶点的关键途径 了解DGC形成的基本病理生理学。在我们的第一个目标中，我们评估激活 正常胃体干细胞中野生型RHOA的表达及其在CDH1缺陷的早期进展中的作用 弥漫性胃癌。我们建议检验我们的假设，即RHOA是WNT5a的中介 对体部干细胞的影响，特别是在cdh1丢失之后。这些结果将立即产生 与DGC启动机制的定义相关，明确告知努力预防和 治疗这些致命的癌症。我们的第二个目标是评估RHOA启动过程中的体细胞突变 和弥漫性胃癌的进展。在这一目标中，我们进一步描述了生物化学和 高度复发性错义的表型效应 DGC中发现的RHOA GTP酶突变。我们还将从功能上验证哪个RHOA 在体外和体内系统中，效应器对这些突变体的致癌活性都是必不可少的。 包括我们新的由CDH1缺失和RhoA突变驱动的DGC小鼠模型。通过这些 研究我们希望确定RHOA介导的转化机制并识别特定的 DGC发病机制的关键途径，与直接潜在相关性的研究结果 以开发新的治疗靶点。