Near‐tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness

Abstract

A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the progressive loss of chromosomes after whole-genome duplication. Here, by using isogenic diploid and near-tetraploid (4N) single-cell-derived clones from the same parental cell lines, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in 4N clones revealed a significant enrichment of transcripts involved in cell cycle and DNA replication. Increased levels of replication stress in 4N cells resulted in DNA damage, impaired proliferation caused by a cell cycle delay during S phase, and higher sensitivity to S phase checkpoint inhibitors. In fact, increased levels of replication stress were also observed in nontransformed, proliferative posttetraploid RPE1 cells. Additionally, replication stress promoted higher levels of intercellular genomic heterogeneity and ongoing genomic instability, which could be explained by high rates of mitotic defects, and was alleviated by the supplementation of exogenous nucleosides. Finally, our data found that 4N cancer cells displayed increased migratory and invasive capacity, both in vitro and in primary colorectal tumors, indicating that tetraploidy can promote aggressive cancer cell behavior.-Wangsa, D., Quintanilla, I., Torabi, K., Vila-Casadesús, M., Ercilla, A., Klus, G., Yuce, Z., Galofré, C., Cuatrecasas, M., Lozano, J. J., Agell, N., Cimini, D., Castells, A., Ried, T., Camps, J. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness.

Whole genome doubling confers unique genetic vulnerabilities on tumor cells

“…4d-e). These data reveal that WGD + tumor cells are more dependent on specific DNA replication factors relative to WGD − tumor cells, perhaps as a means to compensate for increased replication stress induced by tetraploidy 41,42 . These results are particularly significant in therapeutic contexts as gemcitabine and other inhibitors of ribonucleotide reductase represent the standard of care for treatment regimens across multiple cancer subtypes, and biomarkers that can predict sensitivity to gemcitabine hold real prognostic value 43 .…”

Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

“…It has been posited that polyploid tumors with elevated genomic content tend to become resistant to chemotherapy due to rapid tumor evolution (49). In addition, neartetraploid cancer cells have recently been shown to exhibit enhanced invasiveness (50). It will be of interest to determine whether high ploidy status per se is able to contribute to SASPinduced tumor progression.…”

Chromosomal instability-induced senescence potentiates cell non-autonomous tumourigenic effects

“…23), supporting the potential role of polyploidy in tumour development. A recent study reported that near-tetraploid cancer cells exhibited elevated invasiveness and displayed CIN (215), lending support to our findings. Our results therefore describe another mechanism by which polyploidization per se has the potential to contribute to tumourigenesis through senescence and SASP.…”

“…Notably, we observed an enrichment of cells displaying 3 or more signals for these two chromosomes at the invasive fronts compared to cells in the centre region and the normal area, suggesting the existence of near-triploid and near-tetraploid cells at the invasive front. This finding is in line with a recent study that revealed the presence of near-tetraploid cancer cells at the invasive front in primary colorectal tumours, which led to their speculation that tetraploidy could promote the invasiveness and aggressiveness of cancer cells (215). Importantly, our study revealed a correlation of greater deviation from the diploidy with increased incidence of senescence and SASP at the invasion front, indicating that the pro-tumourgenic paracrine effects of SASP from senescent tumour cells might plausibly promote the aggressive behaviour of tumour cells at the invasive front, as described previously in vitro.…”