Interatction between Wnt-mediated inflammation and Mist1+ stem cells in diffuse type gastric cancer

胃癌是世界上最常见的癌症之一。尽管接受了最大限度的治疗，但预后仍然很差。胃癌发生的分子机制尚不完全清楚。CDH-1基因的突变似乎在弥漫型胃癌的发生中起重要作用。由于单纯的CDH-1基因突变不会导致胃癌，同时的炎症促进了这一过程。这种炎症是由wnt介导的GTPase RhoA激活引起的。临床研究表明，rho蛋白突变与胃癌的高发病率相关。目前尚不清楚究竟是哪种分子变化导致了这一过程。来自纽约哥伦比亚大学的王教授小组最近发现了一种新的胃肠道干细胞亚群。这些Mist1+细胞有可能在胃上皮中产生各种类型的细胞，并可能是胃癌的前体细胞。本项目将在Mist1+CreERT2 CDH-1 flox/flox小鼠模型中检测几种抗炎物质（NSAIDs、皮质类固醇、Wnt5特异性抑制剂和RhoA）对胃癌发展的影响。此外，在3d类器官模型中，将研究rhoa突变和肿瘤抑制基因p53突变组合的影响。将进行mrna测序以鉴定由rhoa突变引起的潜在靶结构。通过对这些结构的特异性抑制，将研究这是否会导致肿瘤进展的减少。在第三步，结果将与来自患者集体的临床数据进行比较，并将检查临床相关性。通过将基础研究与临床数据相结合，更好地了解弥漫性胃癌的发展将成为可能。这将为胃癌治疗提供新的诊断和治疗机会的基础。

Gastric cancer is one of the most frequent types of cancers worldwide. Despite maximum therapy prognosis remains poor. The molecular mechanisms of the development of gastric cancer are not completly understood yet. Mutations in the CDH-1 gen seem to play an important role in the genesis of diffuse type gastric cancer. Since solely mutation of the CDH-1 gen does not lead to gastric cancer simultaneous inflammation facilitates this process. This inflammation is induced by Wnt-mediated activation of the GTPase RhoA. Clinical studies have shown that mutations of Rho-proteins are associated with higher incidence of gastric cancer. It is unclear which exact molecular changes lead to this process. The group of Prof. Wang (Columbia University New York) recently identified a novel subpopulation of gastrointestinal stem cells. These Mist1+ cells have the potential to give rise to every type cell in the gastric epithelium and could be precursor cells of gastric cancer. In this project the influence of several anti-inflammatory substances (NSAIDs, corticosteroids, specific inhibitors of Wnt5 and RhoA) on the development of gastric cancer will be tested in a Mist1+CreERT2 CDH-1 flox/flox mouse-model. Additionally in a 3D-organoid model the effect of an combination of RhoA-mutation and a mutation of the tumorsuppressorgen p53 will be investigated. mRNA-sequencing will be performed to identify potential target structures caused by RhoA-mutation. By specific inhibition of these structures it will be investigated if this leads to reduction of tumor progression. In a third step the results will be compared with clinical data from a patient collective and will be checked for clinical relevance. By this connection between basic research and clincical data a better understanding of the development of diffuse type gastric cancer will be possible. This will be the the basis for new diagnostic and therapeutic opportunities in the treatment of gastric cancer.