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Updated: May 19, 2026

Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
07:14

Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations

Published on: September 20, 2019

Centrosome depletion rewires mitosis to impose dependence on the AURKA-TPX2 axis

Zhong Y Yeow, Fang-Chi Chang, Lance Y Xu

    Biorxiv : the Preprint Server for Biology
    |May 18, 2026
    PubMed

    Insights

    Centrosome depletion via PLK4 inhibition creates vulnerabilities in cancer. Loss of PPP6C confers resistance by enhancing Aurora Kinase A (AURKA) activity, revealing new therapeutic targets.

    Area of Science:

    • Cell Biology
    • Cancer Biology
    • Genetics

    Background:

    • Centrosomes are crucial for cell division, and their malfunction is linked to cancer.
    • Polo-like kinase 4 inhibitors (PLK4i) target centrosomes, offering potential cancer therapies.
    • Understanding resistance mechanisms to PLK4i is vital for effective treatment.

    Purpose of the Study:

    • To identify genetic factors influencing sensitivity and resistance to centrosome depletion by PLK4 inhibitors.
    • To elucidate the molecular pathways mediating resistance to centrosome-depleting therapies.

    Main Methods:

    • Genome-wide CRISPR-Cas9 screening was employed to identify genetic suppressors of sensitivity to centrosome depletion.
    • The study utilized cell-based assays to analyze spindle assembly and mitotic organization.
    • Key protein interactions and pathway activations were investigated using molecular biology techniques.

    Main Results:

    • Loss of PPP6C was identified as a general mechanism of resistance to centrosome depletion.
    • This resistance is mediated by increased Aurora Kinase A (AURKA) activation on the spindle, independent of TRIM37.
    • Centrosome depletion forces a dependence on the AURKA-TPX2 axis for spindle assembly.
    • Loss of PPP6C confers resistance, while disrupting the AURKA-TPX2 axis sensitizes cells to PLK4 inhibition.

    Conclusions:

    • Centrosome depletion rewires mitotic organization by altering spindle assembly pathways.
    • The AURKA-TPX2 axis is a critical adaptive pathway following centrosome depletion.
    • Targeting PPP6C or modulating the AURKA-TPX2 axis could enhance the efficacy of centrosome-depleting therapies.

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