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. We developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as 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, more polyploid mice suppressed and more diploid 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. Liver tumor tissues were collected from DEN treated C3h mice, whose liver ploidy were altered by in vivo siRNAs, as well as DEN treated E2f8 WT/Het and KO mice. The tumors were then fixed and the genomic DNA were isolated. The targeted cancer genes in these tumors were sequenced and the mutations were analyzed. Normal liver tissues from three mice were used as normal control.