Dissecting the early events of hepatic carcinogenesis, including understanding hepatocyte tumor transformation, is central to elucidating the underlying pathogenesis of the disease. Recent studies have shown that the development of HCC is intimately linked to a context of genetic, metabolic, and inflammatory alterations that promote a reordering of the division cycle of the hepatocyte. Recently, analyzing cohorts of patients who developed HCC, we have uncovered a transition from physiological polyploidy (tetraploid binuclear hepatocytes) to pathological polyploidy (hyperploid mononuclear hepatocytes) in the damaged hepatic tissue. However, it is not yet known whether this switch in the ploidy spectrum represents a compensation, a cause, or an indirect effect in the pathophysiological processes. In this context, our team is particularly interested to determine whether reprogramming the physiological polyploidy could limit or even prevent tumor progression. We have thus developed transgenic mouse models and Crispr-Cas9 tools to modulate polyploidy in the liver, in order to assess the consequences on intrinsic properties and cell fate of hepatocytes during tumorigenesis process. Furthermore, we will map the ploidy spectrum in human cohorts, according to molecular and pathological classification of HCC (molecular subclasses, histological, genetic, metabolic and immunological features).