In a new study published in EMBO Journal, Nikolaou et al. show that PR-SET7 deficiency in fetal hepatocytes leads to necrosis, and impairs liver organogenesis, while in adults it triggers regenerative processes that give rise to spontaneous development of hepatocellular carcinoma. The mechanism of carcinogenesis involves the elimination of parental hepatocytes with concomitant activation of hepatic ductal progenitors, which undergo oncogenic transformation parallel to differentiation towards the hepatocyte lineage. The ductal progenitors can thus yield cancer stem cells, which confer increased tumor invasiveness and resistance to cytotoxic chemotherapeutics in hepatocellular carcinoma.