TRR 77:  Liver Cancer - From Molecular Pathogenesis to Targeted Therapies

• Subject Area: Medicine ; Biology
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 88491948

• Final Report Year: 2015

Final Report Abstract

Liver cancer is the 2nd most frequent cause of cancer related death worldwide and shows rising incidence. It is the most relevant paradigm of viral, metabolic, and inflammation induced tumourigenesis, but this ideal model situation has not led to satisfactory clinical translation so far. The SFB/TRR77 aimed to investigate the molecular mechanisms that induce and promote liver cancer and to explore their potential for preventive, diagnostic, and therapeutic application. It was the worldwide largest research consortium addressing liver cancer and already in its first funding period made a significant national and international impact by its research data, translational efforts, conferences and workshops, as well as induction of clinical structures at both locations. Key scientific contributions of the SFB/TRR77 were exemplified by the definition of senescence surveillance, a new tumour suppressive mechanism, as well as new pathway interactions and novel protumourigenic mechanisms (e.g. p53 dysregulation), novel mechanisms of HCV oncogenicity, and the theoretical basis for HCC viro-immunotherapy. The SFB/TRR77 has also generated highly valuable research ressources, such as the first mouse model systems for high throughput target and resistance screening and its core HCC collective combined with the coordinated, joint and comprehensive profiling effort. By this, the SFB/TRR77 has induced efficient translational structures for liver cancer at both locations, with strong clinical and diagnostic trial concepts. The structural impact on the international scientific community is visible by the inauguration of the biannual HCC research conference, now adopted by key international scientific organisations (EASL, EACR), the co-inauguration of the international consensus on molecular HCC classification, and many SFB/TRR77-HCC research workshops at different congresses. The success of the consortium is shown by the recruitment of 10 leading academic positions out of the SFB/TRR77 project leaders and many prestigious awards such as the Leibniz award and German cancer awards. Throughout the first funding period, both locations and the subprojects have grown even closer together, forming a tightly woven cooperative network. Efficiency of the many junior researchers support measures (Gerok positions, German liver cancer stipends (MDs), Junior retreats) paid off not only by numerous high class publications but also by successful integration of excellent junior PIs more than filling the gaps. Measures to support gender and family friendly matters were oversigned already in the first funding period.

Publications

• (2010) Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma. Gut 59(10):1416-26
  Boozari B, Mundt B, Woller N, Strüver N, Gürlevik E, Schache P, Kloos A, Knocke S, Manns MP, Wirth TC, Kubicka S, Kühnel F
  (See online at https://doi.org/10.1136/gut.2009.196519)
• (2010) Coffee induces expression of glucuronosyltransferases via the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 139(5):1699-710
  Kalthoff S, Ehmer U, Freiberg N, Manns MP, Strassburg CP
  (See online at https://doi.org/10.1053/j.gastro.2010.06.048)
• (2010) Liver sinusoidal endothelium: a microenvironment dependent differentiation program in rat including the novel junctional protein Leda-1. Hepatology 52(1):313-26
  Géraud C, Schledzewski K, Demory A, Klein D, Kaus M, Peyre F, Sticht C, Evdokimov K, Lu S, Schmieder A, Goerdt S
  (See online at https://doi.org/10.1002/hep.23618)
• (2010) Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma. Hepatology 51(3):857-68
  Pellegrino R, Calvisi DF, Ladu S, Ehemann V, Staniscia T, Evert M, Dombrowski F, Schirmacher P, Longerich T
  (See online at https://doi.org/10.1002/hep.23467)
• (2010) Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids J Hepatol 52(4):570-8
  Erichsen TJ, Aehlen A, Ehmer U, Kalthoff S, Manns MP, Strassburg CP
  (See online at https://doi.org/10.1016/j.jhep.2010.01.010)
• (2010) Targeting of p53-transcriptional dysfunction by conditionally replicating adenovirus is not limited by p53-homologues. Mol Ther 18(5):936-46
  Kühnel F, Gürlevik E, Wirth TC, Strüver N, Malek NP, Müller-Schilling M, Manns MP, Carnero A, Zender L, Kubicka S
  (See online at https://doi.org/10.1038/mt.2009.298)
• (2010) TGF-beta enhances alcohol dependent hepatocyte damage via down-regulation of alcohol dehydrogenase I. J Hepatol 52(3):407-1
  Ciuclan L, Ehnert S, Ilkavets I, Weng HL, Gaitantzi H, Tsukamoto H, Ueberham E, Meindl-Beinker NM, Singer MV, Breitkopf K, Dooley S
  (See online at https://doi.org/10.1016/j.jhep.2009.12.003)
• (2010) The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor initiating cells. J Clin Invest 120(11):3820-33
  Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP
  (See online at https://doi.org/10.1172/jci41959)
• (2011) Deficiency of murine liver sinusoidal scavenger receptors stabilin-1/-2 causes glomerulofibrotic nephropathy via impaired hepatic blood clearance. J Clin Invest 121(2):703-714
  Schledzewski K, Géraud C, Arnold B, Wang S, Gröne H-J, Kempf T, Wollert KC, Straub BK, Schirmacher P, Demory A, Schönhaber H, Gratchev A, Dietz L, Thierse H-J, Kzhyshkowska J, Goerdt S
  (See online at https://doi.org/10.1172/jci44740)
• (2011) Genotyping of the UDP- Glucuronosyltransferase (UGT) 1A7 Gene Revisited. Gastroenterology 140(5):1692-3
  Vogel A, Manns MP, Strassburg CP, Ockenga J, Tukey RH
  (See online at https://doi.org/10.1053/j.gastro.2011.03.036)
• (2011) Mouse hepatic cells support assembly of infectious hepatitis C virus particles. Gastroenterology 141(3):1057-66
  Long G, Hiet MS, Windisch MP, Lee JY, Lohmann V, Bartenschlager R
  (See online at https://doi.org/10.1053/j.gastro.2011.06.010)
• (2011) Non-coding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome Res 21(11):1944-54
  Gutschner T, Baas M, Diederichs S
  (See online at https://doi.org/10.1101/gr.122358.111)
• (2011) Nuclear expression of the ubiquitin ligase seven in absentia homologue (SIAH)-1 induces proliferation and migration of liver cancer cells. J Hepatol. 55(5):1049-57
  Brauckhoff A, Malz M, Tschaharganeh D, Malek N, Weber A, Riener MO, Soll C, Samarin J, Bissinger M, Schmidt J, Longerich T, Ehemann V, Schirmacher P, Breuhahn K
  (See online at https://doi.org/10.1016/j.jhep.2011.02.019)
• (2011) Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis. Hepatology 55(2):455-64
  Joka D, Wahl K, Moeller S, Schlue J, Vaske B, Bahr MJ, Manns MP, Schulze-Osthoff K, Bantel H
  (See online at https://doi.org/10.1002/hep.24734)
• (2011) Recruitment and activation of a lipid kinase by NS5A of the hepatitis C virus is essential for integrity of the membranous replication compartment. Cell Host & Microbe 9(1):32-45
  S Reiss S, Rebhan I, Backes P, Romero-Brey I, Erfle H, Matula P, Kaderali L, Poenisch M, Blankenburg H, Hiet MS, Longerich T, Diehl S, Ramirez F, Balla T, Rohr K, Kaul A, Bühler S, Pepperkok R, Lengauer T, Albrecht M, Eils R, Schirmacher P, Lohmann V, Bartenschlager R
  (See online at https://doi.org/10.1016/j.chom.2010.12.002)
• (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479(7374):547-51
  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
  (See online at https://doi.org/10.1038/nature10599)
• (2011) Strategies for hepatocellular carcinoma therapy and diagnostics: lessons learned from high throughput and profiling approaches. Hepatology 53(6):2112-21
  Breuhahn K, Gores G, Schirmacher P
  (See online at https://doi.org/10.1002/hep.24313)
• (2011) The SCF-Fbxw5 E3-ubiquitin ligase is regulated by Plk4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol. 13(8):1004-9
  Puklowski A, Homsi Y, Keller D, May M, Chauhan S, Kossatz U, Grünwald V, Kubicka S, Pich A, Manns MP, Hoffmann I, Gunczy P, Malek NP
  (See online at https://doi.org/10.1038/ncb2282)
• (2011) Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice. J Clin Invest 121(7):2570-82
  Woller N, Knocke S, Mundt B, Gürlevik E, Strüver N, Kloos A, Boozari B, Schache P, Manns MP, Malek NP, Sparwasser T, Zender L, Wirth TC, Kubicka S, Kühnel F
  (See online at https://doi.org/10.1172/jci45585)
• (2012) Dynamic Oscillation of Translation and Stress Granule Formation Mark the Cellular Response to Virus Infection. Cell Host & Microbe 12: 71-85
  Ruggieri A, Dazert E, Metz P, Hofmann S, Bergeest JP, Mazur J, Bankhead P, Hiet MS, Kallis S, Alvisi G, Samuel C, Lohmann V, Kaderali L, Rohr K, Frese M, Stoecklin G, Bartenschlager R
  (See online at https://doi.org/10.1016/j.chom.2012.05.013)
• (2012) Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 143(3):811-20.e1-15
  Buurman R, Gürlevik E, Schäffer V, Eilers M, Sandbothe M, Kreipe H, Wilkens L, Schlegelberger B, Kühnel F, Skawran B
  (See online at https://doi.org/10.1053/j.gastro.2012.05.033)
• (2012) Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib. Hepatology 57(2):625-36
  Wahl K, Siegemund M, Lehner F, Vondran F, Nüssler A, Länger F, Krech T, Kontermann R, Manns MP, Schulze-Osthoff K, Pfizenmaier K, Bantel H
  (See online at https://doi.org/10.1002/hep.26082)
• (2012) Nuclear Pore Component Nup98 Is a Potential Tumor Suppressor and Regulates Posttranscriptional Expression of Select p53 Target Genes. Mol Cell 48(5):799-810
  Singer S, Zhao R, Barsotti AM, Ouwehand A, Fazollahi M, Coutavas E, Breuhahn K, Neumann O, Longerich T, Pusterla T, Powers MA, Giles KM, Leedman PJ, Hess J, Grunwald D, Bussemaker HJ, Singer RH, Schirmacher P, Prives C
  (See online at https://doi.org/10.1016/j.molcel.2012.09.020)
• (2012) p27Kip1 controls cytokinesis via the regulation of citron kinase activation. J Clin Invest 122(3):844-58
  Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A
  (See online at https://doi.org/10.1172/jci60376)
• (2013) A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153(2):389-401
  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
  (See online at https://doi.org/10.1016/j.cell.2013.03.026)
• (2013) EEF1A2 inactivates p53 via PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology 59(5):1886-99
  Pellegrino R, Calvisi DF, Neumann O, Kolluru V, Wesely J, Chen X, Wang C, Wuestefeld T, Ladu S, Elgohary N, Bermejo JL, Radlwimmer B, Zörnig M, Zender L, Dombrowski F, Evert M, Schirmacher P, Longerich T
  (See online at https://doi.org/10.1002/hep.26954)
• (2013) Post-transcriptional destabilization of the liver-specific long non-coding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). Hepatology 58(5):1703-12
  Hämmerle M, Gutschner T, Uckelmann H, Ozgur S, Fiskin E, Groß M, Skawran B, Geffers R, Longerich T, Breuhahn K, Schirmacher P, Stoecklin G, Diederichs S
  (See online at https://doi.org/10.1002/hep.26537)
• (2013) Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice. Hepatology 58(1):363-73
  Pusterla T, Nèmeth J, Stein I, Wiechert L, Knigin D, Marhenke S, Longerich T, Kumar V, Arnold B, Vogel A, Bierhaus A, Pikarsky E, Hess J, Angel P
  (See online at https://doi.org/10.1002/hep.26395)
• (2013) The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis. Hepatology 58(3):1143-52
  Buitrago-Molina LE, Marhenke S, Longerich T, Sharma AD, Boukouris AE, Geffers R, Guigas B, Manns MP, Vogel A
  (See online at https://doi.org/10.1002/hep.26412)
• (2013). The lipid kinase phosphatidylinositol-4 kinase III alpha regulates the phosphorylation status of hepatitis C virus NS5A. PLoS Pathog 9(5):e1003359
  Reiss S, Harak C, Romero-Brey I, Radujkovic D, Klein R, Ruggieri A, Rebhan I, Bartenschlager R, Lohmann V
  (See online at https://doi.org/10.1371/journal.ppat.1003359)
• (2014) An inducible hepatocellular carcinoma model for preclinical evaluation of anti-angiogenic therapy in adult mice. Cancer Res 74(15):4157-69
  Runge A, Hu J, Wieland M, Bergeest JP, Mogler C, Neumann A, Géraud C, Arnold B, Rohr K, Komljenovic D, Schirmacher P, Goerdt S, Augustin HG
  (See online at https://doi.org/10.1158/0008-5472.can-13-2311)
• (2014) Dysregulated SRF triggers formation of hepatocellular carcinoma. Hepatology 61(3):979-89
  Ohrnberger S, Thavamani A, Braeuning A, Lipka DB, Kirilov M, Geffers R, Authenrieth SE, Römer M, Zell A, Bonin M, Schwarz M, Schütz G, Schirmacher P, Plass C, Longerich T, Nordheim A
  (See online at https://doi.org/10.1002/hep.27539)
• (2014) Endothelial •cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343(6169):416-9
  Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG
  (See online at https://doi.org/10.1126/science.1244880)
• (2014) Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discovery 4(6):730-43
  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
  (See online at https://doi.org/10.1158/2159-8290.cd-13-0782)
• (2014) In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 20(10):1138-46
  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
  (See online at https://doi.org/10.1038/nm.3679)
• (2014) Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. Hepatology 60(4):1241-50
  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, Zornig M, Schirmacher P, Breuhahn K
  (See online at https://doi.org/10.1002/hep.27218)
• (2014) p53 dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158(3):579-92
  Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW
  (See online at https://doi.org/10.1016/j.cell.2014.05.051)
• (2014) Postsurgical adjuvant tumor therapy by combining antiangiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26(6):880-95
  Srivastava K, Hu J, Korn C, Savant S, Teichert M, Kapel SS, Jugold M, Besemfelder E, Thomas M, Pasparakis M, Augustin HG
  (See online at https://doi.org/10.1016/j.ccell.2014.11.005)
• (2014) Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer. Hepatology 60(3):884-95
  Winkler J, Ori A, Holzer K, Sticht C, Dauch D, Eiteneuer EM, Pinna F, Geffers R, Ehemann V, Andres- Pons A, Breuhahn K, Longerich T, Lorenzo Bermejo J, Gretz N, Zender L, Schirmacher P, Beck M, Singer S
  (See online at https://doi.org/10.1002/hep.27207)
• (2014) The Insulin-like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) is an important pro-tumorigenic factor in hepatocellular carcinoma. Hepatology 59(5):1900-11
  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
  (See online at https://doi.org/10.1002/hep.26997)