The Role of RHOA in Diffuse Gastric Cancer

RHOA 在弥漫性胃癌中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目重点关注弥漫性胃癌 (DGC)，这是一种经常致命的癌症，标记为由于其缺乏细胞凝聚力、高度侵入性传播的特征性生长模式明显的转移倾向。该提案建立在 DGC 研究的新进展的基础上，汇集了一个由研究人员组成的协作团队，并就该问题提出了具有挑战性的新发现 RHOA在此病发病机制中的作用及几种新开发的小鼠模型系统。这些数据和资源为实质性推进研究带来了新的机遇这些致命且未被充分研究的癌症。该应用程序背后的第一组数据遵循我们的最近在胃腺中鉴定出一种以 Mist1 表达为标志的新型干细胞群（横山等人，《癌细胞》2015）。这些细胞被证明可产生 DGC 肿瘤抑制因子 Cdh1 的工程缺失。然而，DGC的发育需要分泌 Wnt5a 由干细胞生态位中的细胞产生，Wnt5a 通过激活干细胞生态位中的 GTPase RhoA 发挥作用 Cdh1-无效胃细胞。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 的基因组畸变，要么是高度反复出现的错义 RHOA 或反复融合基因的突变，包括 ARHGAP26（一种 RHOA 调节因子）（TCGA、自然，2014）。在此背景下，描述了 RhoA 在 DGC 发病机制中的功能，涵盖 Cdh1 丢失后野生型 RHOA 的作用以及 RHOA 的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 的表达以及 Cdh1 缺陷的早期进展弥漫性胃癌。我们建议检验我们的假设，即 RHOA 是 Wnt5a 的中介者对体干细胞的影响，特别是在 Cdh1 丢失后。这些结果将立即生效与 DGC 启动机制的定义相关，明确告知预防和预防的努力治疗这些致命的癌症。我们的第二个目标是评估起始阶段的 RHOA 体细胞突变和弥漫性胃癌的进展。为此，我们进一步表征了生化和高度重复错义的表型效应 DGC 中鉴定出的 RHOA GTPase 突变。我们还将在功能上验证 RHOA 效应子对于这些突变体在体外和体内系统中的致癌活性至关重要，包括我们由 Cdh1 丢失和 RhoA 突变驱动的新型 DGC 小鼠模型。通过这些我们希望通过研究确定 RHOA 介导的转化机制并确定具体的对 DGC 发病机制至关重要的途径，具有直接潜在相关性的发现以开发新的治疗靶点。