Asymmetric clustering of centrosomes defines the early evolution of tetraploid cells

Abstract

Tetraploidy has long been of interest to both cell and cancer biologists, partly because of its documented role in tumorigenesis. A common model proposes that the extra centrosomes that are typically acquired during tetraploidization are responsible for driving tumorigenesis. However, this model is inconsistent with the observation that tetraploid cells evolved in culture lack extra centrosomes. This observation raises questions about how tetraploid cells evolve and more specifically about the mechanisms(s) underlying centrosome loss. Here, using a combination of fixed cell analysis, live cell imaging, and mathematical modeling, we show that populations of newly formed tetraploid cells rapidly evolve in vitro to retain a near-tetraploid chromosome number while losing the extra centrosomes gained at the time of tetraploidization.This happens through a process of natural selection in which tetraploid cells that inherit a single centrosome during a bipolar division with asymmetric centrosome clustering are favored for long-term survival.

Patterns of selection against centrosome amplification in human cell lines

“…For instance, it has been observed that after transient centriole elimination, p53-deficient cell populations can seemingly recover their initial distribution of centriole numbers (17,18). Similarly, there are reports of extra centrioles being lost over time in cell populations after induction of cytokinesis failure (19). Since centrosome amplification is typically deleterious for cells, it is likely that centriole numbers in these populations are maintained by a balance of centriole (over)production and negative selection.…”