Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CholangioConcept (Functional in vivo analysis of cholangiocarcinoma development, progression and metastasis.)

Teaser

Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors and therapy resistance inevitably develops upon treatment with cytotoxic drugs or molecular targeted therapies.Cholangiocarcinoma (CCC or bile duct cancer) represents the second most frequent primary...

Summary

Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors and therapy resistance inevitably develops upon treatment with cytotoxic drugs or molecular targeted therapies.

Cholangiocarcinoma (CCC or bile duct cancer) represents the second most frequent primary liver tumor and has emerged as a health problem with sharply increasing incidence rates, in particular of intrahepatic CCC (ICC). The reason for increased CCC incidence remains unclear, but influences of western lifestyle and a resulting altered hepatic metabolism have been discussed. Surgical resection represents the only curative option for the treatment of CCC, however, many tumors are irresectable at the time of diagnosis. CCC represents a highly aggressive and metastatic tumor and currently no effective systemic treatment exists. The overall molecular mechanisms driving CCC formation and progression remain poorly characterized and it thus becomes clear that a detailed molecular characterization of cholangiocarcinogenesis and the identification of robust therapeutic targets for CCC treatment are urgently needed. Taking advantage of our strong expertise in chimaeric (mosaic) liver cancer mouse models and stable in vivo shRNA technology, we here propose a comprehensive and innovative approach to i) dissect molecular mechanisms of cholangiocarcinogenesis, with a particular emphasis on Kras driven ICC development from adult hepatocytes and oncogenomic profiling of ICC metastasis, ii) employ direct in vivo shRNA screening to functionally identify new therapeutic targets for CCC treatment and iii) to characterize the role of the gut microbiome for CCC progression and metastasis.

Work performed

During the first reporting period, all experiments could be conducted, as described in our original grant proposal. In addition to the proposed experiments, we initiated additional experiments to investigate how the microenvironment in chronically damaged livers impact lineage commitment in liver tumorigenesis. We identified a novel and unprecedented mechanism, how lineage commitment is controlled by microenvironmental factors and our data help to explain why intrahepatic cholangiocarcinoma and hepatocellular carcinoma harbour overlapping risk factors such as chronic liver damage, in particular non-alcoholic steatohepatitis (NASH). A first manuscript of our CHOLANGIOCONCEPT is currently in preparation.

Final results

We envision this ERC-funded project will yield important new insights into the molecular mechanisms of CCC development, progression and metastasis. As our work comprises direct and functional strategies to identify new vulnerabilities in CCC, the obtained data will harbor a very high translational potential.