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

Peer-reviewed publications and books
• Rudalska R, Harbig J, Snaebjornsson MT, Klotz S, Zwirner S, Taranets L, Heinzmann F, Kronenberger T, Forster M, Cui W, d’Artista L, Einig E, Hinterleitner M, Schmitz W, Dylawerska A, Kang T-W, Poso A, T. Rosenfeldt MT, Malek NP, Bitzer M, Laufer S, Pichler B, Popov N, Schulze A, Zender L*, Dauch D* (2020) LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat Cancer. DOI: 10.1038/s43018-020-00168-3. *equal contribution and shared last author.
• Moya IM, Castaldo SA, Van den Mooter L, Soheily S, Sansores-Garcia L, Jacobs J, Mannaerts I, Xie J, Verboven E, Hillen H, Algueró-Nadal A, Karaman R, Van Haele M, Kowalczyk W, De Waegeneer M, Verhulst S, Karras P, van Huffel L, Zender L, Marine JC, Roskams T, Johnson R, Aerts S, van Grunsven LA, Halder G (2019) Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science 366:1029-1034.
• Holzer K, Ori A, Cooke A, Dauch D, Drucker E, Riemenschneider P, Andres-Pons A, DiGuilio AL, Mackmull MT, Baßler J, Roessler S, Breuhahn K, Zender L, Glavy JS, Dombrowski F, Hurt E, Schirmacher P, Beck M, Singer S (2019) Nucleoporin Nup155 is part of the p53 network in liver cancer. Nat Commun 10:2147.
• Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O'Connor T, Weston CJ, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Weber A, Heikenwalder M (2019) Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 25:641-655.
• Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwalder M, Wang XW, Bischof O, Zender L (2018) Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562:69-75.
• Georgilis A, Klotz S, Hanley CJ, Herranz N, Weirich B, Morancho B, Leote AC, D'Artista L, Gallage S, Seehawer M, Carroll T, Dharmalingam G, Wee KB, Mellone M, Pombo J, Heide D, Guccione E, Arribas J, Barbosa-Morais NL, Heikenwalder M, Thomas GJ, Zender L, Gil J (2018) PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell 34:85-102.
• Buczak K, Ori A, Kirkpatrick JM, Holzer K, Dauch D, Roessler S, Endris V, Lasitschka F, Parca L, Schmidt A, Zender L, Schirmacher P, Krijgsveld J, Singer S, Beck M (2018) Spatial tissue proteomics quantifies inter- and intratumor heterogeneity in hepatocellular carcinoma (HCC). Mol Cell Proteomics 17:810-825.
• Frey N, Venturelli S, Zender L, Bitzer M (2018) Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol 15:81-95.
• Boege Y, Malehmir M, Healy ME, Bettermann K, Lorentzen A, Vucur M, Ahuja AK, Böhm F, Mertens JC, Shimizu Y, Frick L, Remouchamps C, Mutreja K, Kähne T, Sundaravinayagam D, Wolf MJ, Rehrauer H, Koppe C, Speicher T, Padrissa-Altés S, Maire R, Schattenberg JM, Jeong JS, Liu L, Zwirner S, Boger R, Hüser N, Davis RJ, Müllhaupt B, Moch H, Schulze-Bergkamen H, Clavien PA, Werner S, Borsig L, Luther SA, Jost PJ, Weinlich R, Unger K, Behrens A, Hillert L, Dillon C, Di Virgilio M, Wallach D, Dejardin E, Zender L, Naumann M, Walczak H, Green DR, Lopes M, Lavrik I, Luedde T, Heikenwalder M, Weber A (2017) A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 32:342-359.
• Glück S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, Bridgeman A, Rehwinkel J, Zender L, Ablasser A (2017) Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol 19:1061-1070.





Back to overview