ABSTRACT

Aneuploidy is the condition of having an imbalanced karyotype, which is associated with tumor initiation, evolution, and acquisition of drug-resistant features, possibly by generating heterogeneous populations of cells with distinct genotypes and phenotypes. Multicellular eukaryotes have therefore evolved a range of extrinsic and cell-autonomous mechanisms for restraining proliferation of aneuploid cells, including activation of the tumor suppressor protein p53. However, accumulating evidence indicates that a subset of aneuploid cells can escape p53-mediated growth restriction and continue proliferating in vitro. Here we show that such aneuploid cell lines display a robust modal karyotype and low frequency of chromosomal aberrations despite ongoing chromosome instability. Indeed, while these aneuploid cells are able to survive for extended periods in vitro, their chromosomally unstable progeny remain subject to p53-induced senescence and growth restriction, leading to subsequent elimination from the aneuploid pool. This mechanism helps maintain low levels of heterogeneity in aneuploid populations and may prevent detrimental evolutionary processes such as cancer progression and development of drug resistance.

摘要

非整倍体是核型不平衡的情况，这与肿瘤的发生、进化和耐药特征的获得有关，可能是通过产生具有不同基因型和表型的异质细胞群来实现的。因此，多细胞真核生物进化出一系列用于抑制非整倍体细胞增殖的外在和细胞自主机制，包括肿瘤抑制蛋白 p53 的激活。然而，越来越多的证据表明，一部分非整倍体细胞可以逃脱 p53 介导的生长限制并在体外继续增殖. 在这里，我们展示了这种非整倍体细胞系尽管染色体不稳定，但仍显示出强大的模态核型和低频率的染色体畸变。事实上，虽然这些非整倍体细胞能够在体外存活较长时间，但它们染色体不稳定的后代仍然受到 p53 诱导的衰老和生长限制，导致随后从非整倍体池中消除。这种机制有助于维持非整倍体种群的低水平异质性，并可能防止有害的进化过程，如癌症进展和耐药性的发展。