Whole chromosome loss in tetraploid cells confers tumorigenic potential in a mouse allograft model

Abstract

Whole chromosome gains or losses (aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components but interpretations of these experiments are clouded by the multiple functions of these proteins. Here we used a Cre recombinase-mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12 or 14 in tetraploid immortalized murine embryonic fibroblasts. While the aneuploid cells generally display a growth disadvantage in vitro, they grow significantly better in low adherence sphere-forming conditions and 3 of the 4 lines are transformed in vivo, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo. Thus, these studies demonstrate a causative role for whole chromosome loss in tumorigenesis and may shed light on the early consequences of aneuploidy in mammalian cells.