Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Carolyn Marquis, Cindy L. Fonseca, Katelyn A. Queen, Lisa Wood, Sarah E. Vandal, Heidi L. H. Malaby, Joseph E. Clayton and Jason Stumpff ()
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Carolyn Marquis: University of Vermont
Cindy L. Fonseca: University of Vermont
Katelyn A. Queen: University of Vermont
Lisa Wood: University of Vermont
Sarah E. Vandal: University of Vermont
Heidi L. H. Malaby: University of Vermont
Joseph E. Clayton: BioTek Instruments Inc
Jason Stumpff: University of Vermont

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Chromosomal instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that compromise the mitotic spindle. Thus, CIN cells may respond differently than diploid cells to treatments that target mitotic spindle regulation. Here, we test this idea by inhibiting a subset of kinesin motor proteins involved in mitotic spindle control. KIF18A is required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but is not required in near-diploid cells. Following KIF18A inhibition, CIN tumor cells exhibit mitotic delays, multipolar spindles, and increased cell death. Sensitivity to KIF18A knockdown is strongly correlated with centrosome fragmentation, which requires dynamic microtubules but does not depend on bipolar spindle formation or mitotic arrest. Our results indicate the altered spindle microtubule dynamics characteristic of CIN tumor cells can be exploited to reduce the proliferative capacity of CIN cells.

Date: 2021
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DOI: 10.1038/s41467-021-21447-2

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