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Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate

Asja Guzman, Tatsuya Kawase, Alexander J Devanny

    Biorxiv : the Preprint Server for Biology
    |October 28, 2024
    PubMed

    Insights

    Mutant p53 protein stimulates cancer cell invasion by enhancing cell contractility and extracellular matrix re-organization. This gain of function (GOF) activity is linked to the mevalonate pathway and influenced by the surrounding environment.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cell Biology

    Background:

    • Mutations in the p53 protein can lead to neomorphic gain of function (GOF) activities that promote cancer progression.
    • The concept of mutant p53 GOF has been debated, necessitating further investigation into its mechanisms and implications.

    Purpose of the Study:

    • To investigate the role of mutant p53 in stimulating cancer cell invasion in three-dimensional (3D) environments.
    • To elucidate the molecular mechanisms underlying mutant p53-mediated cancer cell dissemination.

    Main Methods:

    • Utilized various strategies to alter mutant p53 status in different cell lines.
    • Investigated RhoA/ROCK signaling, mevalonate pathway, and extracellular matrix (ECM) interactions.
    • Analyzed cell contractility and ECM re-organization in 3D culture models.

    Main Results:

    • Demonstrated that mutant p53 significantly stimulates cancer cell invasion in 3D environments.
    • Identified enhanced RhoA/ROCK-dependent cell contractility and ECM re-organization mediated by mutant p53.
    • Linked mutant p53 GOF to increased mevalonate pathway activity and RhoA membrane localization.

    Conclusions:

    • Mutant p53 possesses a metabolic GOF activity that drives an invasive cellular phenotype.
    • Mutant p53-mediated invasion is context-dependent, influenced by ECM biomechanical properties and cell-ECM interactions.
    • Findings link mutant p53 GOF to cancer cell dissemination in physiologically relevant settings.

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