Abstract
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.
Highlights
Genomic instability drives evolution, diversification, heterogeneity, and adaptation in many cancers
We present evidence that polyploidy in esophageal adenocarcinoma (EAC) originates from mitotic slippage caused by defects in chromosome attachments during mitosis
The frequency of these defects,
Summary
Diversification, heterogeneity, and adaptation in many cancers. Some cancers present one specific type of CIN, but the two can occur together and numerical CIN can subsequently lead to structural chromosomal aberrations Both aneuploidy and polyploidy are very common in various cancers and numerical CIN is considered a key factor in cancer evolution and diversification, its origin and exact role in cancer onset are still debated [1, 2]. There are four events that, in principle, can lead to polyploidy: cell fusion, genome endoreduplication, cytokinesis failure, or mitotic slippage In the latter case, cells fail to satisfy the mitotic checkpoint and, after sustaining a prolonged arrest, the chromosomes decondense without segregating to the poles and cells re-enter in G1 phase. WGS, RNA-seq, and quantitative immunofluorescence analyses suggested that an imbalance in the amount, and possibly regulation, of proteins involved in the attachment of chromosomes to spindle microtubules could be the molecular mechanism underlying this mitotic failure
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