Single-chromosome Gains Commonly Function as Tumor Suppressors

Abstract

SUMMARY Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes.

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[7,8,18,42] This growth defect is caused by the deregulation of the proteasome, [1,[43][44][45][46] cell metabolism, [47] transcriptome, [41] and the increase in cellular senescence. [42,48] However, not all aneuploidies have the same effect on cells. For example, a trisomy of chromosome 1 confers a much larger growth defect than a trisomy of the smaller chromosome 19, and in general the size of the chromosome anomaly is inversely correlated to the resulting fitness.…”

“…For example, a trisomy of chromosome 1 confers a much larger growth defect than a trisomy of the smaller chromosome 19, and in general the size of the chromosome anomaly is inversely correlated to the resulting fitness. [42] Cancer cells, however, are frequently highly aneuploid. For instance, 61% of all cancerous mouse cell lines tested were aneuploid, [49] and most human cancer cell lines are aneuploid as well.…”

“…[50][51][52] While single chromosome trisomies can act as tumor suppressors (in the euploid HCT 116 colorectal cancer cell line and in mouse xenografts), spontaneous karyotype evolution in these cell lines leads to selection for karyotypes that grow better than their euploid counterparts. [42] Indeed, the frequency of aneuploidy among tumors and cancer cell lines shows that aneuploidy in a cancer setting is quite well tolerated, with certain aneuploidies even being beneficial to cancer cell growth.…”

“…[1,42,53] Culture conditions have been shown to lead to low levels of aneuploidy, [54,55] and these low levels of aneuploidy can lead to the expansion of a clone with an advantageous karyotype. [1] For example 25% of non-cancer mouse cell lines are aneuploid [49] and RPE-1 cells (a human, non-cancer cell line which was initially euploid when harvested) often display clonal gain of chromosome 10q and 12.…”

“…Transient high levels of CIN, however, result in proliferation defects, but are not always lethal. [42] Another important parameter to consider when predicting the response to CIN is the genetic background. For example, CIN induced by SAC alleviation through Mad2 inactivation was reported to be lethal in human cancer cell lines (HeLa and T98G), [22] and in mouse embryonic fibroblasts (MEFs).…”