Department of Pathology, University of Cambridge, Cambridge, UK.
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Cell Death Differ. 2021 Jul;28(7):2179-2193. doi: 10.1038/s41418-021-00745-8. Epub 2021 Mar 1.
Polyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.
多倍体存在于许多癌症类型中，并且越来越被认为是促进染色体不稳定性、基因组进化和癌细胞异质性的重要因素。然而，触发癌细胞多倍体的机制在很大程度上是未知的。在这项研究中，我们使用基因组学和细胞生物学方法在食管腺癌（EAC）细胞系、类器官和肿瘤中研究了多倍体的起源，EAC 是一种高度异质的癌症。我们发现 EAC 细胞和类器官存在特定的有丝分裂缺陷，这与染色体与有丝分裂纺锤体微管的附着问题一致。延时分析证实，EAC 细胞在聚集和排列染色体方面存在问题，这最终可能导致有丝分裂滑步和多倍体。此外，全基因组测序、RNA-seq 和定量免疫荧光分析揭示了几种已知参与有丝分裂过程中染色体动力学的力学和调节的蛋白质的拷贝数、表达和细胞分布的改变。总之，这些结果提供了证据，表明参与染色体与纺锤体微管附着的蛋白质数量失衡是 EAC 中有丝分裂滑步的分子机制。我们的发现，EAC 中多倍体的可能起源是由于染色体附着问题导致的有丝分裂失败，这不仅提高了我们对癌症进化和多样化的理解，也可能有助于 EAC 及其他可能高度异质的癌症的分类和治疗。
