Changes in the chromatin landscape play an important role in the adaptation to targeted therapies in HCC. The research focus of Britta Skawran’s group is based on epigenetic tumor alterations whereas Heike Bantel’s group is focused on the identification of druggable targets for restoring treatment response in HCC. In previous work we observed that certain miRNAs are controlled by HDACs and contribute to tyrosine kinase inhibitor (TKI) resistance in HCC. Based on these findings, the aim of our project is to decipher epigenetic reprogramming in adaptation to HCC molecular therapy. In this respect, the PhD candidate of the first cohort (Skawran group) will apply ATAC-seq and ChIP-seq for profiling of open chromatin and histone modifications in different HCC cell lines and primary HCC cells after HDAC inhibition and/or conventional drug (e.g. TKI) treatment. Therapy-induced cellular phenotypic and transcriptional shifts will be further investigated using mRNA-seq. The MD candidate of the first cohort (Bantel lab) will complement these studies by characterizing HCC cell lines and patient-derived HCC cells for treatment responses (e.g. cell death, survival and proliferation). Based on the bioinformatics analyses, the second cohort´s PhD candidate (Bantel group) seeks to identify novel druggable targets and pathways, which contribute to treatment resistance with the aim of restoring drug response. To this end, we will subject HCC cell lines and patient-derived HCC cells to genetic (e.g. CRISPR-Cas9) and pharmacological (e.g. small molecules, inhibitors) perpetuation studies and will assess their consequences at the functional level. Finally, the MD candidate of the second cohort (Skawran lab) will characterize the drug (e.g. TKI)-induced adaptive state of HCC cells and its modification upon HDAC inhibition with a focus on deregulated miRNAs.