Chromosomally unstable tumor cells specifically require KIF18A for proliferation

SummaryChromosomal instability (CIN), characterized by frequent missegregation of chromosomes during mitosis, is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that comprise the mitotic spindle1–3. Thus, CIN tumor cells may respond differently than normal diploid cells to treatments that target mitotic spindle regulation. We tested this idea by inhibiting a subset of kinesin motor proteins that control spindle microtubule dynamics and mechanics but are not required for the proliferation of near-diploid cells. Our results indicated that KIF18A was required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but was not required in near-diploid cells. CIN tumor cells exhibited mitotic delays, multipolar spindles due to centrosome fragmentation, and increased cell death following inhibition of KIF18A. Sensitivity to KIF18A knockdown was strongly correlated with centrosome fragmentation, which required dynamic microtubules but did 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.

Download Full-text

Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Nature Communications ◽

10.1038/s41467-021-21447-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Carolyn Marquis ◽

Cindy L. Fonseca ◽

Katelyn A. Queen ◽

Lisa Wood ◽

Sarah E. Vandal ◽

...

Keyword(s):

Tumor Cells ◽

Mitotic Spindle ◽

Chromosomal Instability ◽

Triple Negative ◽

Strongly Correlated ◽

Multipolar Spindles ◽

Dynamics And Control ◽

Diploid Cells ◽

And Control ◽

Dynamics Characteristic

AbstractChromosomal 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.

Download Full-text

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

Molecular Biology of the Cell ◽

10.1091/mbc.e08-09-0985 ◽

2009 ◽

Vol 20 (6) ◽

pp. 1639-1651 ◽

Cited By ~ 44

Author(s):

Rania S. Rizk ◽

Kevin P. Bohannon ◽

Laura A. Wetzel ◽

James Powers ◽

Sidney L. Shaw ◽

...

Keyword(s):

Fluorescence Intensity ◽

Mitotic Spindle ◽

Fluorescence Recovery After Photobleaching ◽

Microtubule Dynamics ◽

Microtubule Organization ◽

Spindle Microtubule ◽

Quantitative Immunofluorescence ◽

Spindle Microtubules ◽

Low Levels ◽

Paclitaxel Treatment

Within the mitotic spindle, there are multiple populations of microtubules with different turnover dynamics, but how these different dynamics are maintained is not fully understood. MCAK is a member of the kinesin-13 family of microtubule-destabilizing enzymes that is required for proper establishment and maintenance of the spindle. Using quantitative immunofluorescence and fluorescence recovery after photobleaching, we compared the differences in spindle organization caused by global suppression of microtubule dynamics, by treating cells with low levels of paclitaxel, versus specific perturbation of spindle microtubule subsets by MCAK inhibition. Paclitaxel treatment caused a disruption in spindle microtubule organization marked by a significant increase in microtubules near the poles and a reduction in K-fiber fluorescence intensity. This was correlated with a faster t1/2 of both spindle and K-fiber microtubules. In contrast, MCAK inhibition caused a dramatic reorganization of spindle microtubules with a significant increase in astral microtubules and reduction in K-fiber fluorescence intensity, which correlated with a slower t1/2 of K-fibers but no change in the t1/2 of spindle microtubules. Our data support the model that MCAK perturbs spindle organization by acting preferentially on a subset of microtubules, and they support the overall hypothesis that microtubule dynamics is differentially regulated in the spindle.

Download Full-text

The contribution of αβ-tubulin curvature to microtubule dynamics

The Journal of Cell Biology ◽

10.1083/jcb.201407095 ◽

2014 ◽

Vol 207 (3) ◽

pp. 323-334 ◽

Cited By ~ 135

Author(s):

Gary J. Brouhard ◽

Luke M. Rice

Keyword(s):

Cell Division ◽

Mitotic Spindle ◽

Fundamental Property ◽

Microtubule Dynamics ◽

Cellular Structures ◽

Microtubule Associated Proteins ◽

Associated Proteins ◽

Microtubule Growth ◽

Microtubule Networks ◽

And Control

Microtubules are dynamic polymers of αβ-tubulin that form diverse cellular structures, such as the mitotic spindle for cell division, the backbone of neurons, and axonemes. To control the architecture of microtubule networks, microtubule-associated proteins (MAPs) and motor proteins regulate microtubule growth, shrinkage, and the transitions between these states. Recent evidence shows that many MAPs exert their effects by selectively binding to distinct conformations of polymerized or unpolymerized αβ-tubulin. The ability of αβ-tubulin to adopt distinct conformations contributes to the intrinsic polymerization dynamics of microtubules. αβ-Tubulin conformation is a fundamental property that MAPs monitor and control to build proper microtubule networks.

Download Full-text

Model of Dynamics and Control of Tracking-Searching Head, Placed on a Moving Object

Journal of Automation and Information Sciences ◽

10.1615/jautomatinfscien.v44.i5.40 ◽

2012 ◽

Vol 44 (5) ◽

pp. 38-47 ◽

Cited By ~ 7

Author(s):

I. Krzysztofik ◽

Z. Koruba

Keyword(s):

Moving Object ◽

Dynamics And Control ◽

And Control

Download Full-text

PROJECT ON ELECTRONIC STEERING SYSYTEM

SMART MOVES JOURNAL IJOSCIENCE ◽

10.24113/ijoscience.v4i5.140 ◽

2018 ◽

Vol 4 (5) ◽

pp. 7

Author(s):

Shivam Dwivedi ◽

Prof. Vikas Gupta

Keyword(s):

Steering System ◽

Essential Elements ◽

Variable Pressure ◽

Passenger Cars ◽

Control Techniques ◽

Steering Mechanism ◽

Dynamics And Control ◽

Active Research ◽

Electronic Steering ◽

And Control

As the four-wheel steering (4WS) system has great potentials, many researchers' attention was attracted to this technique and active research was made. As a result, passenger cars equipped with 4WS systems were put on the market a few years ago. This report tries to identify the essential elements of the 4WS technology in terms of vehicle dynamics and control techniques. Based on the findings of this investigation, the report gives a mechanism of electronically controlling the steering system depending on the variable pressure applied on it. This enhances the controlling and smoothens the operation of steering mechanism.

Download Full-text