THESIS
2020
xiv, 152 pages : illustrations (chiefly color) ; 30 cm
Abstract
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...[
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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.
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