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B03: Cooperative and exclusive functions of Hippo pathway effectors in hepato- carcinogenesis

Inactivation of the Hippo pathway followed by the nuclear accumulation of the transcriptional co-activator yes-associated protein (YAP) induces liver tumour formation through the induction of genomic instability and cell proliferation. Increased YAP activity defines HCC patients with poor prognosis and early tumour recurrence. The YAP paralog TAZ (WWTR1) is also regulated by the Hippo pathway. Its oncogenic properties have been demonstrated for breast cancer and very recent work illustrates that TAZ promotes liver fibrosis. Whether YAP and TAZ are regulated by identical cellular features and if they facilitate their biological functions via exclusive or partly identical effector mechanisms in different stages of liver tumour
development is not understood. In three work packages (WPs), we will systematically analyse different levels of YAP and TAZ biology in hepatocarcinogenesis. By using a siRNA screen and proteomics, the common and/or exclusive mechanisms of YAP and/or TAZ regulation and activity will be identified (WP1). To decipher their exclusive and common biological features, we will define target genes regulated by YAP and TAZ alone or in combination by transcriptome expression profiling. The biological relevance of these target genes will be confirmed in vivo by hydrodynamic gene delivery (WP2). In vivo, we will examine if the loss of YAP and/or TAZ affects hepatocyte biology and the cross-talk with other liver cell types under regenerative conditions and during chronic liver damage. Finally, we will analyse if YAP and/or TAZ deficiency affects the tumourinitiating properties of key oncogenes and signalling pathways in liver tumorigenesis (WP3). This project will unravel how and to which extent YAP and TAZ facilitate common and exclusive oncogenic features in different stages of liver tumorigenesis. The results will affect the design of potential therapeutic approaches in patients, which show a dysregulation of the Hippo/YAP/TAZ signalling pathway.

Publications

Samarin J, Laketa V, Malz M, Roessler S, Stein I, Horwitz E, Singer S, Dimou E, Cigliano A, Bissinger M, Falk CS, Chen X, Dooley S, Pikarsky E, Calvisi DF, Schultz C, Schirmacher P, Breuhahn K (2016) PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells. Hepatology 63(3):813-26.
Müller B, Bovet M, Yin Y, Stichel D, Malz M, González-Vallinas M, Middleton A, Ehemann V, Schmitt J, Muley T, Meister M, Herpel E, Singer S, Warth A, Schirmacher P, Drasdo D, Matthäus F, Breuhahn K (2015) Concomitant expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer cells. J Pathol 237:390-401.
Malz M, Bovet M, Samarin J, Rabenhorst U, Sticht C, Bissinger M, Roessler S, Bermejo JL, Renner M, Calvisi DF, Singer S, Ganzinger M, Weber A, Gretz N, Zörnig M, Schirmacher P, Breuhahn K (2014) Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. Hepatology 60:1241-50.
Gutschner T, Hämmerle M, Pazaitis N, Bley N, Fiskin E, Uckelmann H, Heim A, Groβ M, Hofmann N, Geffers R, Skawran B, Longerich T, Breuhahn K, Schirmacher P, Mühleck B, Hüttelmaier S, Diederichs S (2014) Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an important protumourigenic factor in hepatocellular carcinoma. Hepatology 59:1900-11.
Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek N, Quagliata L, Zreik F, Porat RM, Finkelstein R, Reuter H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y, Pikarsky E (2014) Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 4:730-43.
Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Ribback S, Jiang L, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K (2013) Yes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma. Gastroenterology 144:1530- 1542.e12.
Malz M, Aulmann A, Samarin J, Bissinger M, Longerich T, Schmitt S, Schirmacher P, Breuhahn K (2012) Nuclear accumulation of seven in absentia homologue-2 supports motility and proliferation of liver cancer cells. Int J Cancer 131:2016-26.
Singer S, Zhao R, Barsotti AM, Ouwehand A, Fazollahi M, Coutavas E, Breuhahn K, Neumann O, Longerich T, Pusterla T, Powers MA, Leedman PJ, Hess J, Grunwald D, Bussemaker HJ, Singer RH, Schirmacher P, Prives C (2012) Nuclear pore component Nup98 is a potential tumour suppressor and regulates posttranscriptional expression of select p53 target genes. Mol Cell 48:799-810.
Straßburger K, Tiebe M, Pinna F, Breuhahn K, Teleman AA (2012) Insulin/IGF signalling drives cell proliferation in part via Yorkie/YAP. Dev Biol 367:187-196.
Breuhahn K, Schirmacher P (2010) A cellular view of Nf2 in liver homeostasihomeostasis and tumorigenesis. Dev Cell 19:363-4.