The role of the Hippo signaling pathway in gastric tumorigenesis

• Applicant: Dr. Therese Seidlitz
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516146188

Gastric cancer ranks the fifth most common malignant disease and third leading cause of cancer related deaths. Due to the lack of early clinical symptoms, the diagnosis of gastric cancer is often delayed, resulting in a large number of patients with incurable disease. Recently, a robust gastric cancer classification system based on different mutational alterations was described. Here, main tumor drivers were found in the WNT, EGFR, TGFβ, NOTCH, and NFκB signaling pathways. Another pathway that has been supposed to play an important role in gastric cancer tumorigenesis is the Hippo signaling pathway. However, the role of the Hippo pathway remains poorly understood. Mutations of the pathway are found in 25% of gastric cancer patients in combination with alterations of the EGFR, WNT and TGFβ signaling pathways. With the help of the requested project the following two questions shall be answered: (1) Which role plays the Hippo signaling pathway in gastric tumorigenesis? To answer this question, we want to use the recently described, inducible, stomach-specific mouse line. In this mouse line, the Hippo signaling pathway will be inactivated in combination with an inactivation of the WNT, TGFβ pathway or an activation of the EGFR pathway. The models allow the analysis of the gastric epithelium regarding malignant changes of the stomach mucosa over the course of time. The aim of this study is to get a detailed knowledge of the molecular processes in the developing tumors by immunohistochemistry and sequencing analyses. Therapeutic interventions using Hippo pathway specific inhibitors alone or in combination with chemotherapeutic agents will be tested using mouse model derived tumor organoids. (2) Does the Hippo signaling pathway represent a potential treatment target? The aim of this study is to develop therapeutic approaches for Hippo signaling pathway altered gastric carcinomas. Targeted mutagenesis of normal tissue organoids can be used to manipulate target genes in a genetically stable background. In this part of the project, the Hippo signaling pathway will be inactivated in normal human gastric organoids and further mutations in the WNT, EGFR or TGFβ signaling pathway will be introduced. The generated organoid lines will be further molecularly analyzed and the therapeutic approaches defined in project 1 will be validated in these lines. The identified therapy interventions will then be evaluated in patient derived gastric cancer organoids with an active Hippo signaling pathway. This study will help to figure out the functional influence of the Hippo signaling pathway in gastric tumorigenesis and whether the Hippo signaling pathway could act as a potential treatment target for gastric cancer patients in the future.

• DFG Programme: Research Grants