FBS Colloquia No.269Department of Molecular Microbiology , Research Institute for Microbial Diseases

Polyploid hepatocytes give rise to cancers via ploidy reduction

Mammalian somatic cells typically have diploid genomes, but polyploid cells with more than two sets of chromosomes are found abundantly in some tissues such as the liver. Polyploidy is a hallmark of cancer, and proliferation of polyploid cancer cells is closely related to chromosomal instability involved in cancer progression. This raises the question whether proliferating polyploids are prone to cancer via chromosome missegregation. Conversely, polyploidy is reported to suppress tumorigenesis due to their redundant genomes by buffering against genotoxic damages. To examine the involvement of polyploid hepatocytes in carcinogenesis, we performed lineage tracing analysis using mice heterozygous for the Rosa-Confetti multicolor reporter, and found that polyploid hepatocytes readily develop tumors via frequent ploidy reduction. Polyploid hepatocytes reduced their ploidy while robustly proliferating for regeneration, and ploidy reduction enhanced chromosome aberrations during polyploid proliferation. Importantly, oncogenic ploidy reduction was suppressed after continuous proliferation in polyploid hepatocytes, and occurred in an early step of carcinogenesis derived from polyploid hepatocytes. Taken together, these findings suggest that ploidy reduction triggers cancer initiation from polyploid hepatocytes.