The Role of RHOA in Diffuse Gastric Cancer

RHOA 在弥漫性胃癌中的作用

• 批准号: 9904118
• 负责人: Adam Joel Bass
• 金额: $ 67.73万
• 依托单位: DANA-FARBER CANCER INST
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904118
• 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; Epithelium; 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; cell regeneration; cohesion; data resource; effective therapy; fusion gene; gain of function; 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 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.

项目摘要 该项目侧重于弥漫性胃癌（DGC），一种经常致命的癌症，标记为 通过其特征性生长模式，缺乏细胞内聚力，高度侵入性的扩散和 转移的明显倾向。该建议是基于DGC研究的新进展的基础 将一个调查人员的合作团队汇集在一起​​，并提供有关挑衅性的新发现 Rhoa在该疾病的发病机理和几种新开发的小鼠模型中的作用 系统。这些数据和资源带来了新的机会，可以实质上推进研究 这些致命的癌症。本应用程序遵循的第一组数据遵循了我们 最近鉴定出以mist1表达为标志的胃腺中的新型干细胞种群 （Yokoyama等人，癌细胞2015）。这些细胞被证明会引起DGC之后 肿瘤抑制CDH1的工程丧失。但是，DGC的开发需要分泌 干细胞生态裂细胞的Wnt5a，Wnt5a通过激活GTPase RhoA作用 CDH1-无效胃细胞。同时，我们做出了一组新型的基因组发现，发现〜20- 30％的DGCS港口基因组畸变影响Rhoa，要么是高度复发的错过 RhoA或复发融合基因的突变，包括Arhgap26，RhoA调节剂（TCGA，TCGA， 大自然，2014年）。在这种情况下，描述RhoA在DGC发病机理中的功能，跨越 CDH1损失后野生型RhoA的作用和RhoA的致癌功能 突变，成为识别治疗靶标的关键途径和 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 正常胃群干细胞中的野生型RhoA，以及CDH1不足的早期进展 弥漫性胃癌。我们建议检验我们的假设Rhoa是Wnt5a的中介者 对血管干细胞的影响，尤其是在CDH1丢失之后。这些结果将立即 与DGC启动机制的定义相关，清楚地告知了预防和 治疗这些致命的癌症。我们的第二个目标评估了启动中的Rhoa体细胞突变 和弥漫性胃癌的进展。在此目标中，我们进一步描述了生化和 高度复发的错义的表型效应 DGC中鉴定的RhoA GTPase的突变。我们还将在功能上验证哪个Rhoa 效应子对于在体外和体内系统中这些突变体的致癌活性至关重要， 包括我们的新型DGC小鼠模型，由CDH1损失和RhoA突变驱动。通过这些 我们希望确定Rhoa介导的转化的机制并确定特定的研究 对DGC的发病机理至关重要的途径，具有直接潜在相关性的发现 开发新的治疗靶标。