CholangioConcept

Functional in vivo analysis of cholangiocarcinoma development, progression and metastasis

01/09/2015 to 30/08/2020

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 type and currently no effective systemic
therapy regimen 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
expertises 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) to 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. 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 harbor a very high translational potential.