Nuclear destabilisation – a possible genesis of cancer?

This review examines the increasingly prominent role of mechanics within cancer formation and progression. The extremely varied and contradictory genetic landscape of cancer is in stark contrast to the seemingly universal mechanical characteristics of cancer cells and their tumour microenvironment, and mechanics may be a principal unifying trait of this disease. The tight regulation of innate cell mechanical properties raises the possibility that destabilisation of the cell drives tumour formation in an attempt to restore cell mechanical homeostasis. With losses in cell stiffness more pronounced at the cell nucleus, we hypothesise that destabilisation occurs within the nucleus, likely within the nucleosome. Beyond the mechanical properties of the cell, this compromise to the chromatin structure holds significant repercussions for both genetic and epigenetic regulation, providing scope for significant genetic dysregulation and mutation. However, the nature of such genetic events will be dependent upon the region of mechanical destabilisation; thus, introducing greater variability and heterogeneity to genetic changes. We conclude with the hypothesis that cancer has a mechanical genesis, in which cell nuclear destabilisation functions as the enabling hallmark of cancer. It is theorised that both genetic and structural dysfunction stem from this nuclear destabilisation, driving disease pathology and progression.

© 2025 The Author(s). Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.

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