Cancer cells are known for their ability to adopt new characteristics as they move through the body. Many of these changes occur due to epigenetic modifications, which affect how DNA is packaged, rather than mutations in the DNA itself. These modifications pose a challenge for cancer treatment because they can fluctuate and change unpredictably.
Epigenetic alterations have traditionally been attributed to internal cellular mechanisms that add chemical tags to DNA and histones—processes like histone methylation or DNA acetylation. However, new research led by Richard White of Ludwig Oxford and Miranda Hunter of the Memorial Sloan Kettering Cancer Center suggests that the physical environment where these cells reside can also play a critical role in epigenetic transformations.
NatureA study using a zebrafish melanoma model shows that when tumor cells are confined by surrounding tissues, they undergo structural and functional changes. Instead of continuing to proliferate rapidly, these cells activate an 'invasive program,' allowing them to migrate and spread into nearby tissue.
The key player in this transformation is HMGB2: a DNA-bending protein. The research reveals that HMGB2 responds to mechanical confinement-induced stress by binding to chromatin, altering the packaging of genetic material. This action exposes genomic regions linked to invasive behavior, making them newly available for gene expression. Consequently, cells with high levels of HMGB2 become less proliferative but more invasive and treatment-resistant.
The team also discovered that melanoma cells adapt to external pressure by reorganizing their internal skeleton, creating a cage-like structure around the nucleus through the LINC complex—a molecular bridge connecting cell's skeleton to its nuclear envelope—thereby protecting the nucleus from rupture and DNA damage caused by confinement-induced stress.
Nature"Our study demonstrates that cancer cells can quickly switch between different states based on environmental cues," White commented. "Mechanical forces within the tumor microenvironment trigger this switch, making treatment challenging as therapies targeting rapidly dividing cells may miss invasive, drug-resistant ones. By understanding these factors, we might develop therapies to prevent or reverse invasive transformations."
The findings emphasize how the tumor environment shapes cancer cell behavior and shows that physical cues can drive cells' reorganization between growth and invasion states.
Moreover, this study highlights that physical stress is a significant, yet often overlooked driver of epigenetic changes in cancer cells.