A03: Functional genetic dissection of hepatocarcinogenesis in NASH

It is expected that the incidence of liver disease will further rise due to the rapid increase of non-alcoholic fatty liver disease (NAFLD), which e.g. affects 20% of all Americans. NAFL often progresses to nonalcoholic steatohepatitis (NASH), which is predicted to become the most important risk factor for HCC development in the future. The pathogenesis of the various types of chronic liver diseases is complex and multifactorial, but a common feature are repetitive waves of hepatocyte death and compensatory regeneration, which finally lead to an exhaustion of the regenerative capacity of the liver, the development of liver cirrhosis, ending either directly in liver failure or the development of hepatocellular carcinoma (HCC). We will use innovative mouse models and stable RNAi technology to i) functionally test inhibition of the kinases MKK4 and p38alpha (Mapk14) as new therapeutic options for the treatment of NASH and ii) to conduct functional genetic screens to dissect NASH pathogenesis with a particular emphasis on NASH driven HCC development.

Publications

Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M,Reisinger F, Heikenwalder M, Wang XW, Zender L*, Greten TF* (2016) Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. CancerCell 10;30(4):533-547.(*=equal contribution and co-corresponding authors).
Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, YevsaT, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L (2016) A MYC-aurora kinase A protein complex represents an actionable drug target in p53 altered liver cancer. Nat Med 22:744-53.
Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang TW, Hohmeyer A, Pesic M, Leibold J, von Thun A, Schirmacher P, Zuber J, Weiss KH, Powers S, Malek NP, Eilers M, Sipos B, Lowe SW, Geffers R, Laufer S, Zender L (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 20(10):1138-46.
Wuestefeld T, Pesic M, Rudalska R, Dauch D, Longerich T, Kang TW, Yevsa T, Heinzmann F, Hoenicke L, Hohmeyer A, Potapova A, Rittelmeier I, Jarek M, Geffers R, Scharfe M, Klawonn F, Schirmacher P, Malek NP, Ott M, Nordheim A, Vogel A, Manns MP, Zender L (2013) A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153(2):389-401.10