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Functional Genomics

 

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Our research in RNAi-based functional genomics especially focuses on the identification of new cancer genes and therapeutic targets in therapy-resistant solid tumors. For such studies, clinically relevant mouse tumor models, which closely resemble the human disease, are established in the CCC-T. Specifically, CCC-T scientists are combining mosaic mouse models with stable RNAi technology to dissect tumor suppressor networks in gastrointestinal tumors and to identify and validate new therapeutic target genes.
 

 

For example, taking advantage of stable RNAi technology, we characterized YAP and cIAP as liver cancer oncogenes and explored their role for tumor maintenance (Zender et al., Cell 2006).

 

RNAi-based functional genomics is an emerging and very promising field in cancer research. At CCC-T we have recently started a novel research project to unravel mechanisms of therapy resistance and to identify new therapeutic targets in gastrointestinal tumors. Genetic heterogeneity and complexity are hallmarks of metastatic solid tumors, in which therapy resistance inevitably develops upon treatment with current cytotoxic drugs or targeted therapies. Research groups at CCC-T share a strong background in RNAi-based functional genomic screening to identify new therapeutic targets in therapy resistant gastrointestinal tumors. Specifically, innovative preclinical mosaic cancer mouse models are combined with stable short hairpin RNA technology to dissect tumor suppressor networks in gastrointestinal tumors and to identify and validate new therapeutic target genes. Together with a limited number of other laboratories worldwide, we have the expertise to conduct RNAi screens for new target genes directly in orthotopic and immunocompetent mouse models in vivo (Zender et al., Cell 2008, Wuestefeld et al., Cell 2013). We take advantage of our in vivo RNAi screening platform to characterize molecular mechanisms of drug resistance in HCC, a prototype of a therapy-resistant solid tumor. For example, negative selection pooled shRNAs screens were recently conducted in murine HCCs in vivo to identify gene products that mediate resistance against the multikinase inhibitor sorafenib. Direct in vivo RNAi screening pinpointed a new kinase as a crucial mediator of sorafenib resistance. Induction of the kinase candidate was identified as a crucial survival mechanism of sorafenib-treated murine and human hepatomas and kinase inhibition rendered cells sensitive to sorafenib treatment and resulted in increased survival of HCC-bearing mice. Importantly, highly selective inhibitors against the identified kinase are currently in the phase of clinical testing as anti-inflammatory drugs. In collaboration with our Center for Clinical Trials we are therefore currently preparing a clinical trial for the combined use of these inhibitors and sorafenib for the treatment of advanced HCC.

Contact

Prof. Dr. Lars Zender

Prof. Dr. Lars Zender
Scientific Director, CCC Tübingen-Stuttgart
Chair, Dept. of Internal Medicine VIII - Clinical Tumor Biology
phone +49 7071 29-84113
fax +49 7071 29-2095
 

 

Most relevant peer-reviewed publications from the last 5 years

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

 

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 re¬presssion by oncogenic MYC shape tumour-specific gene expression profiles. Nature. 2014 Jul 24;511(7510):483-7

 

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

 

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

 

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 28;483(7391):608-12

 

Wang J, Sun Q, Morita Y, Jiang H, Groß A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wüstefeld T, Schrezenmeier H, Hofmann WK, Ju Z, Kestler HA, Zender L, K. Rudolph KL. Batf defines a differentiation checkpoint limiting hematopoietic stem cell self-renewal in response to DNA damage, Cell, 2012 Mar 2;148(5):1001-14

 

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 9;479(7374):547-51

 

Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, Grütter C, Werz O, Rauh D, Stehle T, Laufer SA. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2011

Dec 25;8(2):141-3


 

 

Last update: 03.11.2016






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