Project Details
Projekt
The role of the adhesion molecule L1CAM in the epithelial-mesenchymal transition (EMT) and metastasis of pancreatic ductal adenocarcinoma
Applicant
Professorin Dr. Susanne Sebens
Subject Area
Gastroenterology
Term
from 2008 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 81036907
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a pronounced tumor stroma and an early metastasis which essentially limits curative treatment options of these patients. In the process of metastasis, the TGF-beta1 induced epithelial-mesenchymal-transition (EMT) and probably the adhesion molecule L1CAM play an important role. Thus, human H6c7 pancreatic ductal epithelial that have been cocultered with pancreatic myofibroblasts (PMFs) are characterized by a mesenchymal phenotype along with an increased L1CAM expression. Moreover, these cells exhibit an enhanced tumorigenic potential leading to formation of pancreatic tumors and liver metastasis in vivo. Disseminated H6c7 cells in liver metastasis show a different expression profile of L1CAM and EMT markers than H6c7 cells in primary tumors. Accordingly, the impact of the cellular microenvironment on EMT and the reverting process, the mesenchymal-epithelial reverting transition (MErT), shall be investigated. It shall be further investigated how these alterations functionally impact on cell adhesion, migration, proliferation and apoptosis, the central processes of tumor cell dissemination and formation of metastases. In addition, a deeper understanding of the role of L1CAM in these scenarios is intended. For these purposes, H6c7 and PDAC cells will be cultured in the presence of PMFs or different hepatic stromal cells (representative for the cellular microenvironment of the primary tumor and metastases) and the cells will be functionally and phenotypically analysed regarding the expression of L1CAM and EMT markers. Furthermore, an EMT/MErT profile will be generated from tumor cells in primary tumors and liver metastasis as well as in blood and bone marrow of PDAC patients and correlated with clinical parameters. Overall the findings of this project will deepen our understanding of the metastatic process in PDAC patients and will help to better characterize disseminated tumor cells to improve therapeutic strategies for advanced PDAC patients.
DFG Programme
Research Grants
International Connection
Austria
