The stem cell ubiquitin ligase RNF43 in gastric homeostasis, DNA damage response and carcinogenesis: from biological function to application as biomarker

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Gastric cancer is the third leading cause of cancer-related deaths worldwide, and the 5-year survival rate across all stages is still low (around 20%) due to metastasis, recurrence and insufficient therapeutical options. The ring finger ubiquitin ligase RNF43, initially described as a tumor suppressor in colorectal cancer, has been found to be frequently mutated in gastric cancer and showed high proclivity for truncating mutations of up to 54% in tumours presenting with microsatellite instability (MSI). Recently, RNF43 has been shown to interact with p53, and a possible link between RNF43 and DNA damage response was postulated. Thus, RNF43 might be involved in the response to chemotherapy or radiation, and mutations might represent an interesting marker for gastric cancer management and patient stratification. Based on several preliminary data which support such assumption, in the current project we propose to analyse the function of endogenous RNF43 in gastric cells in vitro and in vivo by knocking out or overexpressing mutated RNF43 in cell lines as well as in mice. We have already generated mice bearing RNF43 point mutations or deletions, which will be thoroughly characterized in this project. Given the fact that gastric cancer mostly arises upon chronic H. pylori infection, we are planning to investigate the function of RNF43 in the context of H. pylori infection. Finally, we propose to assess whether RNF43 status influences the responsiveness of gastric tumors towards chemotherapy or radiation using cancer cell lines as well as organoids from normal stomach and gastric tumour samples of patients. In summary, our data may help to establish the analysis of RNF43 mutation status as a tool for the selection of therapeutic regimens to treat gastric cancer patients