Cell and Nuclear Size are Associated with Chromosomal Instability and Tumorigenicity in Cancer Cells that Undergo Whole Genome Doubling

Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. Here, we showed that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.