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

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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.