The polyploid state plays a tumor suppressive role in the liver

Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization normally occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate the function of polyploidy while avoiding irreversible manipulations of essential cell cycle genes, we developed multiple orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as in vivo knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no impact of ploidy alterations on liver function, metabolism, or regeneration, hyperpolyploid mice suppressed and hyperdiploid mice accelerated tumorigenesis in mutagen and high fat induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that ploidy differentially protected the liver from distinct genomic aberrations. Our work suggests that polyploidy evolved to prevent malignant outcomes of liver injury.