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

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.

高达80%的人类癌症，尤其是实体瘤，其肿瘤细胞存在染色体数目异常，即非整倍性(aneuploidy)，该现象通常与显著的染色体不稳定性紧密相关。部分肿瘤中的非整倍性由一条或多条染色体的错分离所导致，而非整倍性也可起源于二倍体细胞经全基因组加倍(whole genome doubling)生成的固有不稳定四倍体细胞的增殖过程。癌症基因组测序项目的近期研究成果表明，近40%的肿瘤在肿瘤发生的某一阶段曾发生全基因组加倍，但其对癌症表型的贡献以及对恶性生长的促进益处仍未明确。本研究针对癌性与非转化型p53阳性人类细胞，探究了全基因组加倍所产生的生物学效应。通过单核苷酸多态性阵列(SNP array)分析与多色核型分析，我们发现诱导产生的全基因组加倍会引发程度不一的非整倍性。我们观察到，染色体不稳定性(CIN)是全基因组加倍的常见结局，但并非必然结果。该染色体不稳定性表型伴随有对有丝分裂错误的耐受性增强，这一效应由p53信号通路的抑制所介导。此外，促凋亡因子如iASPP与cIAP2的表达均出现下调。进一步研究发现，全基因组加倍可使细胞对广谱化疗药物产生耐药性，且即便在非转化型p53阳性人类细胞中，也能促进非锚定依赖性生长。综上，全基因组加倍可为恶性增殖提供多维度的有利条件。本研究结果为阐释全基因组加倍如何促进肿瘤发生、并与癌症患者不良预后相关提供了新的见解。