A novel murine model for the functional in-vivo analysis of cholangiocarcinoma: a screen for new tumor suppressor genes and a detailed characterization of the model.

• Applicant: Privatdozentin Dr. Anna Lena Saborowski
• Subject Area: Gastroenterology
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 202496315

Cholangiocarcinoma (CC) is a malignant epithelial neoplasm that arises from the biliary tree and accounts for 10-20% of deaths related to hepatobiliary malignancies. Limited treatment options lead to a 5-year survival rate of less than 5%. The development of urgently needed new therapeutic strategies for CC will require a better understanding of genes and cellular pathways involved in this fatal disease. To facilitate in-vivo investigation of cholangiocarcinogenesis, I have developed a transplantable mosaic mouse model of CC that histologically closely resembles human disease. RNA-interference (RNAi) technology enables me to rapidly introduce genetic alterations.The first aim of the proposed research is to conduct a detailed characterization of the CC mouse model. I will investigate the metastatic behavior and the influence of the tumor microenvironment in chemotherapy response. Furthermore, I will delineate the role of the pro-inflammatory cytokine Interleukin-6 (IL-6) in cholangiocarcinogenesis by selectively depleting IL-6 production in either the tumor cells or the surrounding tissue. The second aim of this proposal is to perform an oncogenomics based screen for new tumor suppressor genes in CC using RNAi technology in combination with the CC mouse model. This screen will involve use of a short hairpin RNA (shRNA) library, which I designed, containing shRNAs directed against 160 genes that were found deleted in human CC tumor specimens. After application of low complexity shRNA pools, the progenitor cells will be transplanted orthotopically into recipient mice and acceleration of tumor growth will be assessed. Enriched shRNAs targeting candidate tumor suppressor genes will be identified by high-throughput sequencing. Candidates will be subjected to in-vivo validation and further characterization using the CC mouse model.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Scott Lowe, Ph.D.