Defining the role of hepatocellular carcinoma-related epigenetic alterations driving immune evasion
Abstract:
Epigenetic alterations frequently occur in liver cancer and significantly impair tumor-directed immune responses by both, facilitating resistance to the attack of cytotoxic immune cells while concomitantly modulating function and composition of immune cells in the tumor microenvironment. Based on the potential reversibility of epigenetic modifications and, thus, epigenetic driven immune escape mechanisms the characterization of these mechanisms might be of particular importance for the development of novel therapeutic approaches. Here, we will analyze the role of two HCC-associated key epigenetic regulators, DNMT1 and SIRT6, and their related modifications in tumor-directed immune responses.
Principal investigators:
Univ.-Prof. Dr. rer. nat. Susanne Strand
I. Medizinische Klinik und Poliklinik
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17 9782
sstrand@uni-mainz.de
Web: http://www.unimedizin-mainz.de/1-med/wissenschaftler/grundlagenforschung/prof-susanne-strand.html
Jun.-Prof. Dr. med. Jens Marquardt
I. Medizinische Klinik und Poliklinik
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17 4161
marquarj@uni-mainz.de
Web: http://www.unimedizin-mainz.de/1-med/patienten/mitarbeiter/portraits/marquardt.html
Postdoc:
Dr. Carolin Czauderna
Doctoral candidate:
Julia Schäfer
Project-related publications:
Steinmetz C, Kashyap A, Zhivkova N, Alizor H, Ernst I, Gottfried-Brand D, Janssen H, Teufel A, Schulze-Bergkamen H, Lotz J, Kuball J, Theobald M, Heise M, Lang H, Galle P, Strand D, Strand S (2017) Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation. Hepatology, doi: 10.1002/hep.29072
Marquardt JU*, Fischer K*, Baus K, Kashyap A, Ma S, Krupp M, Linke M, Teufel A, Zechner U, Strand D, Thorgeirsson SS, Galle PR, Strand S. (2013) SIRT6 dependent genetic and epigenetic alterations are associated with poor clinical outcome in HCC patients. Hepatology 58(3):1054-64 (*Joint first authors)
Su Z, Kuball J, Barreiros AP, Gottfried D, Antunes Ferreira A, Theobald M, Galle PR, Strand D, Strand S, (2006) Nitric oxide promotes resistance to tumor suppression by CTLs. J Immunol 176: 3923-3930
Strand S, Vollmer P, van den Abeelen L, Gottfried D, Heid H, Kuball J, Theobald M, Galle PR, Strand D (2004) Cleavage of CD95 by Matrix-Metalloproteinase-7 induces apoptosis resistance in tumor cells Oncogene 23: 3732-3736
Strand S, Hofmann WJ, Hug H, Müller M, Otto G, Mariani SM, Stremmel W, Krammer PH, and Galle PR (1996) Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand expressing tumor cells - A mechanism of immune evasion? Nature Med. 2: 1361-1367
Castven C., Fischer M., Becker D., Heinrich S., Andersen JB., Strand D., Sprinzl MF., Strand S., Czauderna C., Heilmann S., Roessler S., Weinmann A., Wörns MA., Thorgeirsson SS., Galle PR., Matter MS., Lang H., Marquardt JU. (2017) Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas. Oncotarget Mar 15. doi: 10.18632/oncotarget.16231
Andersen JB, Factor VM, Marquardt JU, Raggi C, Lee YH, Seo D, Conner EA, Thorgeirsson SS. (2010) An integrated genomic and pharmacoepigenomic approach predicts therapeutic response of zebularine in human liver cancer. Sci Transl Med 2(54): 54ra77
Raggi C, Factor VM, Seo D, Holczbauer A, Gillen MC, Marquardt JU, Andersen JB, Durkin M, Thorgeirsson SS (2014) Epigenetic reprogramming modulates malignant properties of human liver cancer Hepatology 59(6): 2251-62
Marquardt JU, Seo D, Andersen JB, Gillen MC, Kim MS, Conner EA, Factor VM, Park YN, Thorgeirsson SS (2014) Sequential analysis of hepatocarcinogenesis indicates late stage acquisition of malignant traits. J Hepatol 60(2): 346-53
Kaji K., Factor VM., Andersen JB., Durkin ME., Marquardt JU., Tomokuni A., Matter MS., Hoang T., Conner EA., Thorgeirsson SS (2016) DNMT1 is essential for postnatal liver histogenesis and regeneration. Hepatology Aug;64(2):582-98