Pressure from surrounding tissues activates invasive programs in cancer cells. This mechanical stress rewires epigenetic regulation.
Cancer cells are notoriously adaptable, capable of shifting their characteristics as they spread throughout the body. Many of these shifts stem from epigenetic changes, which influence how DNA is organized and expressed rather than altering the genetic code itself. Because such changes are reversible and can switch on and off, they are particularly challenging to target in cancer therapies.
Traditionally, epigenetic alterations were believed to result mainly from processes inside the cell, such as the chemical tagging of DNA and its associated histone proteins, including mechanisms like histone methylation or DNA acetylation. However, a new study led by Richard White of Ludwig Oxford and Miranda Hunter of Memorial Sloan Kettering Cancer Center, published in Nature, reveals that the physical conditions surrounding cancer cells are also powerful triggers of epigenetic change.
Working with a zebrafish model of melanoma, White, Hunter, and their collaborators found that tumor cells under tight physical confinement undergo dramatic structural and functional shifts. Instead of multiplying rapidly, these cells switch to a program of “neuronal invasion,” which equips them to migrate and infiltrate surrounding tissue.
Central to this transformation is HMGB2, a protein that bends DNA. The study shows that HMGB2 responds to confinement-induced mechanical stress by binding to chromatin, reshaping how genetic material is packaged. This reorganization exposes genome regions linked to invasive behavior, making them available for expression. As a result, cells with elevated HMGB2 lose some of their proliferative capacity but become more invasive and resistant to therapy.
