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类型之一。尽管进行了最大限度的治疗，但预后仍然很差。目前对胃癌发生的分子机制尚不完全清楚。CDH-1基因突变似乎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，因此同时的炎症促进了这一过程。这种炎症是由Wnt介导的GTP酶RhoA的激活引起的。临床研究表明，Rho蛋白的突变与胃癌的高发病率有关。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(纽约哥伦比亚大学)的团队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细胞中分化为各种类型的细胞，可能是胃癌的前体细胞。在本项目中，将在Mist1 CreERT2 CDH-1 FLOX/FLOX小鼠模型上测试几种抗炎物质(非甾体抗炎药、皮质类固醇、WNT5和RhoA的特异性抑制剂)对胃癌发生的影响。此外，在3D有机物模型中，将研究RhoA突变和肿瘤抑制基因P53突变的组合的影响。将进行mRNA测序，以确定RhoA突变引起的潜在靶结构。通过对这些结构的特异性抑制，将研究这是否会减缓肿瘤的进展。在第三步中，结果将与来自患者集体的临床数据进行比较，并将检查其临床相关性。通过基础研究和临床数据之间的这种联系，将有可能更好地了解弥漫型胃癌的发展。这将为胃癌的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.