Exploring the interplay of endocytosis with the methionine cycle in pancreatic ductal adenocarcinoma initiation and progression.

• Applicant: Professor Dr. Roland M. Schmid, since 5/2022
• Subject Area: Gastroenterology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251579498

The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal among human tumors. More than 95% of patients with such tumors die within 5 years of diagnosis. The activation of mutated, constitutive active KrasG12D in 90% of all human PDACs has led to the hypothesis that oncogenic KrasG12D is required for tumor initiation. However, signaling and cellular events taking place downstream of KrasG12D are still poorly understood. Emerging evidence suggests that PDAC development is unlikely to occur without the preceding presence of acino-ductal metaplasia (ADM).Our preliminary work has shown that endocytosis plays a pivotal role during ADM development and that key enzymes of the methionine cycle interact with early endosomes. In addition, we have shown that enzymes that are part of the methionine cycle are involved in the development of the ADM that eventually leads to pancreatic tumor development.Based on the preliminary work, we hypothesize a link between endocytosis and the methionine cycle in acinar cells expressing oncogenic KrasG12D causing ADM development and eventually PDAC. Thus, we intend to investigate the following questions:1. Does modulation of the methionine cycle either cause or inhibit ADM? 2. Does modulation of the methionine cycle affect PDAC development?3. Is there a link between between endocytosis and the methionine cycle?To address these questions, we aim to use: conditional mouse models; three dimensional explants of pancreatic tissue; molecular and cell biological methods; an advanced in vivo synthetic lethality screening of genes involved in the endocytosis and in the methionine cycle.In this research proposal we seek to extend our knowledge of the role of the methionine cycle in PDAC development, with particular focus on its interaction with the endocytic compartment. We aim to gain insights into the mechanism of PDAC development and to establish a body of long-term basic knowledge for new diagnostic and/or therapeutic strategies.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Clara Lubeseder-Martellato, until 5/2022