Cancer's deadliest feature is its ability to adapt and spread. While genetic mutations are a known driver, a new study highlights a powerful, reversible, and non-genetic switch: physical pressure.
Published in Nature, research from the Ludwig Institute for Cancer Research and Memorial Sloan Kettering Cancer Center shows that when cancer cells are mechanically squeezed by surrounding tissues, they undergo a profound transformation. They stop rapidly dividing and instead activate an invasive, "neuronal" program to escape.
The key to this dangerous switch is the HMGB2 protein. The study, using a zebrafish melanoma model, demonstrates that HMGB2 acts as a mechanical sensor. When cells feel confined, HMGB2 binds to chromatin, the complex of DNA and proteins, and alters its architecture. This epigenetic change exposes genes linked to invasiveness, effectively reprogramming the cell for migration and survival.
"This flexibility poses a major challenge for treatment, as therapies targeting rapidly dividing cells may miss those that have transitioned to an invasive, drug-resistant phenotype," explained senior author Richard White.
Furthermore, the team discovered that cells under pressure build a protective, cage-like structure around their nucleus, involving the LINC complex. This shield helps prevent DNA damage from the physical stress, allowing the cell to survive its dangerous transformation.
The findings fundamentally shift our understanding of cancer progression by showing that physical forces are a potent driver of epigenetic change. By identifying HMGB2 and this mechanical pathway, the research opens new avenues for therapies aimed at preventing or reversing the switch to an invasive state, potentially making cancers less aggressive and more treatable.