Suppressing the evolution of liver cancer into highly aggressive forms

A major obstacle in treating liver cancer is their enormous inter- and intratumoral heterogeneity, forming a spectrum from pure hepatocellular
carcinoma (HCC) over mixed and intermediate tumors to pure cholangiocarcinoma (CCA), a cancer with cholangiocyte (bile duct)
characteristics1. Unfortunately, during progression and treatment, HCCs can adapt and amplify their cholangiocytic character, which makes them more
aggressive and therapy resistant1. Our preliminary data and published reports indicate that this adaptation is driven by epigenetic reprograming2.
However, how HCC cells acquire cellular plasticity and shift towards cholangiocytic phenotypes is not known. In our project we use mouse
models to characterize molecular pathways that drive cancer cell plasticity and transdifferentiation, and test inhibitors of key modulators to redirect the
fate of cancer cells towards a less aggressive cell type. These experiments will direct new approaches to prevent the evolution of liver cancer cells into
more aggressive forms and to trigger their elimination.