Aneuploidy is a hallmark of cancer. Abnormally high chromosome numbers are prevalently detected in many tumours and are often associated with poor prognosis and therapeutic efficiency. Although polyploidy can be deliberately induced under experimental settings, polyploidy is scarcely maintained in mammalian cells as a result of frequent cell cycle arrest and multipolar cell division. More work remains to be accomplished to resolve the inconsistency between clinical observations and laboratory experiments on the long-term maintenance of polyploidy. In this study, I screened HeLa cells with a panel of antimitotic drugs and identified Eg5 as a target to control cell fate following polyploidisation. Eg5 inhibition prior to mitotic slippage diverges polyploid cells from the canonical...[ Read more ]

Aneuploidy is a hallmark of cancer. Abnormally high chromosome numbers are prevalently detected in many tumours and are often associated with poor prognosis and therapeutic efficiency. Although polyploidy can be deliberately induced under experimental settings, polyploidy is scarcely maintained in mammalian cells as a result of frequent cell cycle arrest and multipolar cell division. More work remains to be accomplished to resolve the inconsistency between clinical observations and laboratory experiments on the long-term maintenance of polyploidy. In this study, I screened HeLa cells with a panel of antimitotic drugs and identified Eg5 as a target to control cell fate following polyploidisation. Eg5 inhibition prior to mitotic slippage diverges polyploid cells from the canonical cell fate in committing multipolar cell division. Instead, immunofluorescence microscopy revealed that Eg5 inhibition during mitotic slippage, in spite of centrosome amplification detected in polyploid cells, activates centrosome clustering to coalescent excess spindle poles into pseudo-bipolar spindle assembly. Bipolar division, confirmed by flow cytometry and live cell time-lapse imaging, allows cancer cells to tolerate and stably propagate higher ploidy even after a prolonged culturing. Remarkably, this study demonstrates that Eg5 inhibition can promote polyploidisation up to stable octoploids (8N) and rescue polyploids committing to multipolar cell division. Collectively, these results indicate that Eg5 inhibition during polyploidisation is sufficient to promote the long-term maintenance of large genome in cancer cells and extend our understanding on the influence of cell fate determination after the adaptation to prolonged mitotic arrest.