This excerpt from a scientific article details a study investigating how mechanical confinement in the tumor microenvironment drives phenotype switching in melanoma cells from a proliferative to an invasive and drug-resistant state. Using models including zebrafish melanoma and human cell lines, the researchers demonstrate that physical pressure causes melanoma cells to adopt an undifferentiated, neuronal-like identity. This process is mediated by the DNA-bending protein HMGB2, which is upregulated by confinement via a mechanism involving the LINC complex protein nesprin 2 and a stabilizing perinuclear acetylated tubulin cage. The resulting increase in HMGB2 stabilizes its interactions with chromatin, thereby increasing accessibility at loci associated with a neuronal and invasive phenotype, ultimately linking mechanical stress to melanoma progression and therapeutic resistance.

References:

• Hunter M V, Joshi E, Bowker S, et al. Mechanical confinement governs phenotypic plasticity in melanoma[J]. Nature, 2025: 1-11.