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.


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