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Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling. | LitMetric

AI Article Synopsis

  • - The study investigates how certain mutations in the p53 protein can lead to increased cancer cell invasion, contradicting previous views on mutant p53's role in cancer progression.
  • - Researchers found that mutant p53 enhances the ability of cancer cells to invade their surroundings by modulating the RhoA/ROCK signaling pathway and affecting the organization of the extracellular matrix (ECM).
  • - The findings suggest that the invasive effects of mutant p53 are influenced not just by the cells themselves but also by the mechanical properties of the ECM, highlighting the complex interactions during cancer metastasis.

Article Abstract

Unlabelled: Certain mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) re-organization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent pro-invasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with an invasive cellular phenotype in physiologically relevant and context-dependent settings.

Significance: This study addresses the contribution of mutant p53 to the process of cancer cell dissemination in physiologically relevant three-dimensional environments - a key characteristic of metastatic disease. Several mutant p53 proteins display pro-oncogenic activity with respect to cancer cell invasion in 3D environments via mevalonate pathway-dependent Rho/ROCK signaling axis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11507699PMC
http://dx.doi.org/10.1101/2024.10.13.618100DOI Listing

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