Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Carolyn Marquis,Sarah E Vandal,Jason Stumpff,Cindy L Fonseca,Katelyn A Queen,Lisa Wood,Heidi L H Malaby,Joseph E Clayton

doi:10.1038/s41467-021-21447-2

Carolyn Marquis, Sarah E Vandal + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-21447-2

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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.

Highlights

Chromosomal instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that compromise the mitotic spindle
KIF18A KD significantly reduced the proliferation of all three triple-negative breast cancer (TNBC) cell lines but did not affect the growth of diploid MCF10A cells (Fig. 1a, b)
To determine if this trend holds in other tumor cell types, we measured proliferation in colorectal cancer (CRC) cells categorized as displaying either chromosomal instability (CIN) or microsatellite instability (MSI), a form of genomic instability arising from defective DNA repair in near-diploid tumor cells[16]

Summary

Introduction

Chromosomal instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that compromise the mitotic spindle. 1234567890():,; Genetic instability is a common feature of tumor cells, and a large number of tumor cells exhibit frequent loss or gain of chromosomes[1] This chromosomal instability (CIN) is primarily attributable to defects leading to abnormal interactions between chromosomes and mitotic spindle microtubules, which in turn increase chromosome segregation errors[2,3,4,5,6,7]. One explanation for the apparent paradox presented by failed mitotic targeting strategies and the effective therapeutic results seen with paclitaxel is that paclitaxel may not kill tumor cells in vivo by preventing mitotic progression This idea is supported by work demonstrating that clinically relevant doses of paclitaxel induce abnormal, multipolar divisions in tumors, rather than preventing mitotic division altogether[11,13]. Our results demonstrate that the majority of CIN tumor cells tested depend on the kinesin-8 motor KIF18A to maintain bipolar spindle integrity and promote proliferation

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