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

胃癌是世界范围内最常见的癌症类型之一。尽管最大限度的治疗预后仍然很差。胃癌发生的分子机制尚未完全清楚。CDH-1基因突变可能在弥漫型胃癌的发生中起重要作用。由于CDH-1基因的单独突变不会导致胃癌，同时炎症促进了这一过程。这种炎症是由Wnt介导的GTdR RhoA活化诱导的。临床研究表明，Rho蛋白突变与胃癌发病率增高有关。目前还不清楚是哪些确切的分子变化导致了这一过程。王教授（哥伦比亚大学纽约）的研究小组最近发现了一种新的胃肠道干细胞亚群。这些Mist 1+细胞具有分化为胃上皮各型细胞的潜能，可能是胃癌的前体细胞。在该项目中，将在Mist 1 + CreERT 2 CDH-1 flox/flox小鼠模型中测试几种抗炎物质（NSAID、皮质类固醇、Wnt 5和RhoA的特异性抑制剂）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突变的组合的效果。将进行mRNA测序以鉴定RhoA突变引起的潜在靶结构。通过特异性抑制这些结构，将研究这是否导致肿瘤进展的减少。在第三步中，将结果与来自患者集体的临床数据进行比较，并检查临床相关性。通过基础研究与临床资料的结合，将有助于更好地了解弥漫型胃癌的发展。这将为胃癌治疗提供新的诊断和治疗机会。

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.