B05: The role of epigenetic modifiers in liver cancer plasticity

Mutations in epigenetic modifiers are among the most frequent genetic events in human cancer. However, their impact in tumorigenesis is not well understood. Previous work revealed that epigenetic changes caused by defined mutations, e.g. in Isocitrate dehydrogenase (IDH), can lead to cell fate changes in the liver and consequently tumor development of intrahepatic cholangiocarcinomas (ICCs), suggesting an important role of these genes in tumor suppression. Surveying human whole genome sequencing data from hepatocellular carcinoma (HCC) patients and ICC patients we identified two epigenetic modifiers, BAP1 and PBRM1, predominantly mutated in ICC samples, suggesting they could play an important role in this disease. In this project we will define the role of these two genes in liver tumorigenesis and liver cell plasticity using unique mouse model systems specifically tailored to address these questions. By
utilizing CRISPR/Cas9 genome editing and Tet-regulatable shRNA transgenic mouse strains we will first dissect the function of BAP1 and PBRM1 on tumor suppression in chemically- and genetically-driven liver cancer mouse models. Additionally, we will probe the function of BAP1 and PBRM1 depletion on liver cell fate under physiologic and malignant conditions. Next, we will define specific target genes important for tumor suppression of each epigenetic regulator by transcriptomic and epigenetic profiling and will translate our findings in human carcinogenesis. Finally, we will use these data to assess specific vulnerabilities of BAP1- and PBRM1-deficient cancer cells in a focussed CRISPR screen and subsequent in vivo validation experiments. The project outlined here will help to understand the impact of epigenetic regulators in liver cancer and could potentially pinpoint to targeted therapies for a genetically defined subset of liver tumors.


a) Peer-reviewed publications and books
• Breinig M, Schweitzer AY, Herianto AM, Revia S, Schaefer L, Wendler L, Cobos Galvez A, Tschaharganeh DF (2019) Multiplexed orthogonal genome editing and transcriptional activation by Cas12a. Nat Methods 16:51-54.
• Moon SH, Huang CH, Houlihan SL, Regunath K, Freed-Pastor WA, Morris JP 4th, Tschaharganeh DF, Kastenhuber ER, Barsotti AM, Culp-Hill R, Xue W, Ho YJ, Baslan T, Li X, Mayle A, de Stanchina E, Zender L, Tong DR, D'Alessandro A, Lowe SW, Prives C (2019) p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell 176:564-580.e19.
• Zafra MP, Schatoff EM, Katti A, Foronda M, Breinig M, Schweitzer AY, Simon A, Han T, Goswami S, Montgomery E, Thibado J, Kastenhuber ER, Sánchez-Rivera FJ, Shi J, Vakoc CR, Lowe SW, Tschaharganeh DF, Dow LE (2018) Optimized base editors enable efficient editing in cells, organoids and mice. Nat Biotechnol 36:888-893.
• 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 67:1842-2856.
• Faletti L, Peintner L, Neumann S, Sandler S, Grabinger T, Mac Nelly S, Merfort I, Huang CH, Tschaharganeh D, Kang TW, Heinzmann F, D'Artista L, Maurer U, Brunner T, Lowe S, Zender L, Borner C (2018) TNFα sensitizes hepatocytes to FasL-induced apoptosis by NFκB-mediated Fas upregulation. Cell Death Dis 9:909.
• Kastenhuber ER, Lalazar G, Houlihan SL, Tschaharganeh DF, Baslan T, Chen CC, Requena D, Tian S, Bosbach B, Wilkinson JE, Simon SM, Lowe SW (2017) DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci U S A 114:13076-13084.
• Méndez-Lucas A, Li X, Hu J, Che L, Song X, Jia J, Wang J, Xie C, Driscoll PC, Tschaharganeh DF, Calvisi DF, Yuneva M, Chen X (2017) Glucose catabolism in liver tumors induced by c-MYC can be sustained by various PKM1/PKM2 ratios and pyruvate kinase activities. Cancer Res 77:4355-4364.
• Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hüser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M (2017) Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS. Cancer Cell 3:771-789.