The Role of RHOA in Diffuse Gastric Cancer

RHOA 在弥漫性胃癌中的作用

• 批准号: 10416081
• 负责人: CHANNING J. DER
• 金额: $ 78.78万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416081
• 关键词: Automobile Driving; Bass; Belief; Biochemical; Biochemistry; 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; Structure; 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; 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.

项目摘要 该项目的重点是弥漫性胃癌（DGC），一种常见的致命癌症， 由于其特有的生长模式，缺乏细胞凝聚力，高度侵入性扩散， 有明显的转移倾向这一建议建立在DGC研究的新进展基础上， 汇集了一个合作小组的调查人员与挑衅性的新发现， RHOA在该病发病机制中的作用及几种新的小鼠模型 系统.这些数据和资源带来了新的机会，以实质性地推进研究， 这些致命的未被充分研究的癌症。该应用程序的第一组数据遵循我们的 Mist 1表达标记的胃腺中新的干细胞群的最新鉴定 （Yokoyama等人，Cancer Cell 2015）。这些细胞被证明在以下情况下产生DGC 肿瘤抑制因子Cdh 1的工程缺失。然而，DGC的发展需要分泌 Wnt 5a通过激活干细胞龛中的GT3 RhoA发挥作用， CDH 1- null胃细胞。与此同时，我们进行了一系列新的基因组发现，发现~20- 30%的DGC具有影响RHOA的基因组畸变， RHOA或复发融合基因的突变，包括ARHGAP 26，RHOA调节因子（TCGA， Nature，2014）。在这种情况下，描绘RhoA在DGC发病机制中的功能， 野生型RHOA在Cdh 1丢失后的作用和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 野生型RHOA在正常胃体干细胞中的表达，以及在Cdh 1缺陷型胃体干细胞的早期进展中的表达。 弥漫性胃癌我们建议验证我们的假设，即RHOA是Wnt 5a的介导者 对身体干细胞的影响，特别是在Cdh 1丢失后。这些结果将立即 与DGC启动机制定义的相关性，明确告知预防和 治疗这些致命的癌症。我们的第二个目的是评估RHOA体细胞突变在启动 和扩散性胃癌的进展。在这个目标中，我们进一步表征了生物化学和 高重复性错义表型效应 DGC中鉴定的RHOA GT3突变。我们还将在功能上验证哪个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是必需的， 包括我们的新型DGC小鼠模型，该模型由Cdh 1缺失和RhoA突变驱动。通过这些 我们希望通过这些研究来确定RHOA介导的转化机制，并确定特定的 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 新的治疗靶点的发展。