Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells

Abstract

Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer.

The Role of Aneuploidy in Cancer Evolution

“…Such tumors display a much higher rate of copynumber gain and losses, most of which is acquired post genome-doubling (Zack et al 2013;Dewhurst et al 2014). Experiments with various cell lines showed that tetraploid cells are also much more tolerant to segregation errors than their diploid precursors, without prior mutations (Dewhurst et al 2014;Kuznetsova et al 2015). Deleterious genetic alterations are most likely buffered in a tetraploid background, providing a genetic environment into which a wider range of genetic makeups can be explored.…”

“…Tetraploid cells, by virtue of their higher CIN rate and tolerance (Dewhurst et al 2014), also display greater resistance to a broad range of compounds (Lee et al 2011;Dewhurst et al 2014;Kuznetsova et al 2015). One explanation for this phenomenon is that CIN allows the maintenance of various karyotypes, and the one(s) conferring a proliferative advantage expand on selection.…”

Identification of genes that are essential to restrict genome duplication to once per cell division

“…Aneuploid cells have either gained or lost entire chromosomes or parts of chromosomes. They exist in up to 80% of cancers, and they are associated with a poor prognosis for recovery [3]. Moreover, genome sequencing reveals that up to 37% of all tumors have transitioned through a polyploid state during their development [4], suggesting that tumorigenesis is accelerated by transition through the inherently unstable polyploid state.…”

Tetraploidy and CIN: a dangerous combination

“…3 In this issue of Cell Cycle, Storchova and colleagues confirm these results, and elegantly extend their analysis to search for a mechanistic basis for CIN tolerance in tetraploid cells. 4 In this study, the authors investigate genome stability in tetraploid clones derived from HCT-116 and hTERT-RPE1 cells. Intriguingly, tetraploidy resulted in a CIN+ phenotype (increased chromosome missegregation, aneuploidy, and segregation error tolerance) in all HCT-116 tetraploid clones, but in only one of 3 hTERT-RPE1 tetraploid clones.…”

“…This paper by Storchova and colleagues adds to the now growing body of evidence showing that tetraploidy is an important driver of CIN in cancer. 4 For the first time CIN is shown to arise in immortalised non-transformed human cells after tetraploidisation, raising intriguing questions about when this phenotype might arise in the transition from pre-invasive to malignant disease in patients. Intriguingly, the presence of extra centrosomes does not seem to influence the level of chromosome missegregation in tetraploid cells.…”