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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.


Peer-reviewed publications and books
• Thomann S, Weiler SME, Marquard S, Rose F, Ball CR, Tóth M, Wei T, Sticht C, Fritzsche S, Roessler S, de la Torre C, Ryschich E, Ermakova O, Mogler C, Kazdal, D, Gretz N, Glimm H, Rempel, E, Schirmacher P, Breuhahn K (2020) YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis. Cancer Res 80:5502-5514.
• Marquard S, Thomann S, Weiler SME, Bissinger M, Lutz T, Sticht C, Tóth M, de la Torre C, Gretz N, Straub BK, Marquardt J, Schirmacher P, Breuhahn K (2020) Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator inhibitor-1 (PAI-1) expression in hepatocarcinogenesis. Cell Commun Signal 18:166.
• Weiler SME, Lutz T, Bissinger M, Sticht C, Knaub M, Gretz N, Schirmacher P, Breuhahn K (2020) TAZ target gene ITGAV regulates invasion and feeds back positively on YAP and TAZ in liver cancer cells. Cancer Lett 473:164-175.
• Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, Heikenwalder M (2020) A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. J Hepatol 72:960-975.
• Wei T, Weiler SME, Tóth M, Sticht C, Lutz T, Thomann S, De La Torre C, Straub B, Merker S, Ruppert T, Marquardt J, Singer S, Gretz N, Schirmacher P, Breuhahn K (2019) YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells. Oncogene 38:5541-5550.
• 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.
• Drucker E, Holzer K, Pusch S, Winkler J, Calvisi DF, Eiteneuer E, Herpel E, Goeppert B, Roessler S, Ori A, Schirmacher P, Breuhahn K, Singer S (2019) Karyopherin α2-dependent import of E2F1 and TFDP1 maintains protumorigenic stathmin expression in liver cancer. Cell Commun Signal 17:159.
• Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, Uhrig S, Kriegsmann M, Weiss KH, Breuhahn K, Mehrabi A, Weber TF, Wilkens L, Straub BK, Rosenwald A, Schulze F, Brors B, Froehling S, Pellegrino R, Budczies J, Schirmacher P, Stenzinger A (2019) RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours. Gut 68:1287-1296.
• Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García-Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze-Bergkamen H, Köhler BC (2019) Nuclear translocation of RELB is increased in diseased human liver and promotes ductular reaction and biliary fibrosis in mice. Gastroenterology 156:1190-1205.
• Wan S, Meyer AS, Weiler SME, Rupp C, Tóth M, Sticht C, Singer S, Thomann S, Roessler S, Schorpp-Kistner M, Schmitt J, Gretz N, Angel P, Tschaharganeh DF, Marquardt J, Schirmacher P, Pinna F, Breuhahn K (2018) Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology 67:1842-1856.