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B01: Linking chronic inflammation with tumor suppressor gene inactivation in liver cancer

The high mortality rate of HCC is mainly caused by metastasis or de novo multifocal tumor formation in the diseased liver. Genomic alterations are a hallmark of tumor formation in most solid tumor types. In HCC, high heterogeneity in terms of number of genomic alterations per tumor and of regions affected by genomic alterations has been observed. In previous work using an integrative genomic and transcriptomic approach, we showed that in HCC loss of chromosome 8p is observed in 45% of tumors and is associated with poor patient outcome. Interestingly, chromosome 8p deletion has also been observed in about 50% of breast, lung and colon carcinomas and the involved deletions mostly involve the whole chromosome 8p arm. In addition, we identified SORBS3 and SH2D4A as two novel tumor suppressor genes on chromosome 8p and showed that the gene expression profiles of patients with chromosome 8p deletion exhibit expression patterns characteristic of inhibition of interleukin-6 (IL-6) signaling. It has been shown that IL-6 signaling is a key activated pathway in inflammation, and is especially involved in development and metastasis of HCC. Taken together these findings suggest that SORBS3 and SH2D4A may modulate IL-6 signaling. Recently, we were able to demonstrate that SH2D4A and SORBS3 functionally collaborate to inhibit IL-6 mediated STAT3 signaling and HCC cell growth. However, the molecular mechanisms of modulation of STAT3 signaling by SH2D4A and SORBS3 are still unclear. In addition, SH2D4A and SORBS3 directly interact with STAT1 protein and high expression of SH2D4A or SORBS3 leads to enhanced IFNγ/STAT1 signaling. These findings are consistent with a tumor suppressive function of STAT1 which had been reported in multiple tumor entities. Thus, the objective of this application is to elucidate the role of chromosome 8p tumor suppressor genes in IL-6/STAT3 signaling. To this end, we will 1) functionally dissect how SORBS3 and SH2D4A modulate IL-6/STAT3 signaling and the cross-talk of STAT3 and STAT1 at the molecular level, 2) investigate the loss of chromosome 8p regions, harboring SORBS3 and SH2D4A, engineered by CRISPR/Cas9 in immortalized hepatocytes and 3) determine the influence of SORBS3 and SH2D4A on the tumor microenvironment, immune cell infiltration, and cytokine profiles in a murine orthotopic HCC model, in human HCC tissues,and co-culture experiments.

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Publications

a) Peer-reviewed articles and books
• Goeppert B, Stichel D, Toth R, Fritzsche S, Loeffler MA, Schlitter AM, Neumann O, Assenov Y, Vogel MN, Mehrabi A, Hoffmann K, Köhler B, Springfeld C, Weichenhan D, Plass C, Esposito I, Schirmacher P, von Deimling A, Roessler S. Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis. Gut. doi: 10.1136/gutjnl-2020-322983.
• Ploeger C*, Huth T*, Sugiyanto RN, Pusch S, Goeppert B, Singer S, Tabti S, Hausser I, Schirmacher P, Désaubry L, Roessler S (2020) Prohibitin directly interacts with the tumor suppressor gene SH2D4A and with STAT3 and exerts a crucial role in hepatocellular carcinoma. Cell Death Dis 11:1023.
• Ostroumov D, Duong S, Wingerath J, Woller N, Manns MP, Timrott K, Kleine M, Ramackers W, Roessler S, Nahnsen S, Czemmel S, Dittrich-Breiholz O, Eggert T, Kühnel F, Wirth T (2020) Transcriptome profiling identifies TIGIT as a marker of T cell exhaustion in liver cancer. Hepatology. doi: 10.1002/hep.31466.
• Luiken S, Fraas A, Bieg M, Sugiyanto R, Goeppert B, Singer S, Ploeger C, Warsow G, Marquardt J, Sticht C, De La Torre C, Pusch S, Mehrabi A, Gretz N, Schlesner M, Eils R, Schirmacher P, Longerich T, Roessler S (2020) NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 39:3128–3144.
• 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.
• Goeppert B, Toth R, Singer S, Albrecht T, Lipka DB, Lutsik P, Brocks D, Baehr M, Muecke O, Assenov Y, Gu L, Endris V, Stenzinger A, Mehrabi A, Schirmacher P, Plass C, Weichenhan D*, Roessler S* (2019) Integrative analysis defines distinct prognostic subgroups of intrahepatic cholangiocarcinoma. Hepatology 69:2091-2106.
• 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.
• 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.
• Ploeger C, Waldburger N, Fraas A, Goeppert B, Pusch S, Breuhahn K, Wang XW, Schirmacher P, Roessler S (2016) Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology 64:828-42.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Roessler S, Edeline J, Schirmacher P*, Coulouarn C* (2021) Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer. J Hepatol S0168-8278(21)00007-6.





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