Epigenetic and Genetic interplay in Liver Cancer

Objective

Liver cancer is a leading cause of mortality worldwide, yet its cellular origins are poorly understood. The Valier lab (host) has shown that a population of hepatocyte-cholangiocyte bi-phenotypic cells expands during the progression of chronic liver disease (MASLD). Chronic injury leads to epigenetic erosion, which has been recognised as a cancer hallmark. Whilst genetic drivers of liver cancer have been identified, the capacity of epigenetic erosion and cancer-driver mutations to cooperate to drive cellular plasticity has not been explored. This fellowship will build on my expertise in somatic mutation acquisition in chronically inflamed tissues to: O1. Determine the capacity of liver cancer-driver mutations to promote epigenetic remodelling and cellular plasticity, and O2. Determine the capacity of epigenetic remodelling to drive cellular plasticity and enhance the function of liver cancer-driver mutations. The Vallier lab is uniquely positioned to host this project, having established protocols to derive and transdifferentiate human cholangiocyte and hepatocyte organoids. Using CRISPR, I will introduce cancer-driver mutations in organoids from healthy and epigenetically eroded end-stage liver disease tissue and evaluate the impact on plasticity between hepatocytes and cholangiocytes. This fellowship will give me expertise in liver biology, patient-derived organoids, genome engineering, epigenomic profiling, as well as bioinformatic skills. Communication and outreach will be supported by the international and translational environment of the BIH at Charité and the MPI-MG. I will acquire an interdisciplinary collaborative network and develop leadership skills under the mentorship of Prof. Dr. Vallier. By combining access to rare liver organoids with my background in mutation dynamics, the project will uncover early determinants of liver cancer that may inform strategies for early detection, and equip me to transition into an independent academic research career.