The role of the Wnt5a/Frizzled5 signaling axis in the development and therapy of helicobacter-associated gastric cancer arising from epithelial stem cells

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Gastric cancer is one of the most frequent types of gastrointestinal cancer worldwide and the outcome is still poor. The surgical resection is the only curative treatment but the majority of the patients receives preoperative chemotherapy. The response rates to this therapy vary in each patient and until today, there is no reliable parameter predicting the response to preoperative therapy. One potential reason for this different response are tumor stem cells. In the last years several potential stem cell population in the gastric epithelium have been described. In this project we aim to investigate the relevance of the FZD5/Wnt5a signaling axis on the development of gastric cancer. In a first step we will stain human tissue for FZD5 and perform in-situ hybridisation for Wnt5a since immunhistochemical detection of Wnt5a is quite challenging. Previous studies have shown innate lymphoid cells type 2 (ILC-2) as a major source of Wnt5a in the stomach so that we will perform staining for these cells as well. These parameters will correlated with the clinical patient data to evaluate the potential progonostic value of the expression of these markers in human gastric cancer. In a next step we will investigate this signaling axis in different murine models in detail. For these experiments, different mouse models are available in which these genes can be knocked out. These animals will be infected with Helicobacter ssp. that induce an inflammation. Chronic infection with Helicobacter represents one of the major risks factors for the development of gastric cancer in humans. Using FACS-isolation we will analyse FZD5+ stem cells and investigate the stemness using organoids. Additionally, we aim to identify potential therapeutic targets using RNA-sequencing. The results from these experiment will be validated and tested for the prognostic relevance using the human samples. This project will help to improve the understanding of gastric cancer development following chronic infection with Helicobacter and will provide important knowledge for the improvement of therapy in gastric cancer patients.