How Mechanical Pressure Influences Epigenetic Changes in Cancer Cells

Recent research reveals that physical forces within the tumor microenvironment can significantly influence cancer cell behavior by triggering epigenetic modifications. A study led by Richard White and Miranda Hunter at Ludwig Oxford and the Memorial Sloan Kettering Cancer Center, published in Nature, demonstrates that cellular confinement—mechanical pressure exerted by surrounding tissues—acts as a catalyst for epigenetic reprogramming in melanoma cells. When tumor cells are tightly confined, they undergo structural and functional transformations, shifting from a proliferative state to an invasive phenotype. A key player in this process is HMGB2, a DNA-bending protein that responds to mechanical stress by binding to chromatin and modifying gene packaging. This exposes genomic regions linked to invasiveness, allowing cancer cells to become more migratory and resistant to treatments. Additionally, melanoma cells respond to external pressure by remodeling their internal skeleton, forming a protective cage around the nucleus through the LINC complex, which safeguards against nuclear rupture and DNA damage under stress. These mechanical cues prompt cytoskeletal reorganization, further supporting the invasive transformation. The findings emphasize how physical forces within the tumor microenvironment are potent drivers of epigenetic changes and phenotypic plasticity, contributing to treatment resistance. Understanding these mechanotransduction pathways opens new avenues for therapies aimed at preventing the invasive and drug-resistant states of cancer cells, addressing one of the major challenges in oncology.