RESEARCH
Liver regeneration/disease, epigenetics, aging
One hallmark of aging is the accumulation of senescent cells; this parallels the regenerative decline and the rise in cancer incidences. The reduction in the regenerative capacity is linked to epigenetic changes in the genome. Chronic liver damage together with an attenuated regenerative response can lead to cirrhosis, liver failure or cancer. So far the only curative treatment for liver failure is organ transplantation. Unfortunately the amount of donor organs is limited and does not meet the demand.
We are working in the field of regenerative biology with the focus on understanding the process of liver regeneration. We are especially interested in identifying and understanding epigenetic and age dependent changes, resulting in regenerative decline and liver disease. Using our recently developed new system for performing in vivo RNAi screens in mice, in combination with state-of-the-art omics technology we want to identify new therapeutic targets to improve endogenous liver regeneration and/or attenuate the age dependent decline in the regenerative capacity. The ultimate goal is to translate this knowledge into new therapies to suppress liver failure and allow healthy aging in humans.
Selected Publications
- Jedicke N, Struever N, Aggrawal N, Welte T, Manns MP, Malek NP, Zender L, Janciauskiene S, Wuestefeld T "α-1-antitrypsin inhibits acute liver failure in mice." Hepatology 2014 Jun ; 59(6) : 2299-308 Epub 2014 Apr 28 Abstract
- Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wüstefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E, Eilers M "Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles." Nature 2014 Jul 24 ; 511(7510) : 483-7 Epub 2014 Jul 9 Abstract
- 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 "In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer." Nat Med 2014 Oct ; 20(10) : 1138-46 Epub 2014 Sep 14 Abstract
- 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 "A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration." Cell 2013 Apr 11 ; 153(2) : 389-401 Abstract
- Zender S*, Nickeleit I*, Wuestefeld T*, Sörensen I, Dauch D, Bozko P, El-Khatib M, Geffers R, Bektas H, Manns MP, Gossler A, Wilkens L, Plentz R, Zender L, Malek NP "A critical role for notch signaling in the formation of cholangiocellular carcinomas." Cancer Cell 2013 Jun 10 ; 23(6) : 784-95 Epub 2013 May 30
*authors contributed equally to the work Abstract
- Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J "A complex secretory program orchestrated by the inflammasome controls paracrine senescence." Nat Cell Biol 2013 Aug ; 15(8) : 978-90 Epub 2013 Jun 16 Abstract
- Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL "A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage." Cell 2012 Mar 2 ; 148(5) : 1001-14 Epub 2012 Mar 1 Abstract
- Liu L, Ulbrich J, Müller J, Wüstefeld T, Aeberhard L, Kress TR, Muthalagu N, Rycak L, Rudalska R, Moll R, Kempa S, Zender L, Eilers M, Murphy DJ "Deregulated MYC expression induces dependence upon AMPK-related kinase 5." Nature 2012 Mar 29 ; 483(7391) : 608-12 Abstract
- Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L "Senescence surveillance of pre-malignant hepatocytes limits liver cancer development." Nature 2011 Nov 24 ; 479(7374) : 547-51 Epub 2011 Nov 9 Abstract