AUGUST 27, 2025, NEW YORK - Cancer cells are notoriously flexible, taking on new features as they move around the body. Many of these changes are due to epigenetic modifications, which influence how DNA is packaged, and not due to mutations in the DNA itself. Such modifications are difficult to target for cancer therapy because they are reversible and can flip on and off.
Epigenetic changes have traditionally been thought to arise from internal cellular processes that result in the chemical tagging of DNA and its histone protein packaging-such as histone methylation or DNA acetylation. But now a new study led by Ludwig Oxford's Richard White and Miranda Hunter of the Memorial Sloan Kettering Cancer Center and reported in the current issue of Nature shows that the physical environment in which these cells land is also a key instigator of epigenetic transformation.
Using a zebrafish model of melanoma, White, Hunter and their colleagues show that when tumor cells are tightly confined by surrounding tissues, they undergo structural and functional changes. Rather than continuing to divide rapidly, the cells activate a program of 'neuronal invasion', enabling them to migrate and spread into the surrounding tissue.
At the center of this transformation is HMGB2: a DNA-bending protein. The study demonstrates that HMGB2 responds to the mechanical stress of confinement by binding to chromatin, altering how genetic material is packaged. This exposes regions of the genome linked to invasiveness, making them newly available for gene expression. As a result, cells with high levels of HMGB2 become less proliferative but more invasive and resistant to treatment.
The team also found that melanoma cells adapt to this external pressure by remodeling their internal skeleton, forming a cage-like structure around the nucleus. This protective shield involves the LINC complex, a molecular bridge that connects the cell's skeleton to the nuclear envelope, helping to protect the nucleus from rupture and DNA damage caused by confinement-induced stress.
"Cancer cells can rapidly switch between different states, depending on cues within their environment," White explained. "Our study has shown that this switch can be triggered by mechanical forces within the tumor microenvironment. 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. By identifying the factors that are involved in this switch, we hope to able to develop therapies that prevent or even reverse the invasive transformation."
The findings highlight the role of the tumor microenvironment in shaping cancer cell behavior, showing how physical cues can drive cells to reorganize their cytoskeleton, nucleus and the architecture of their genomic packaging to shift between states of growth and invasion.
Most notably, however, the study also demonstrates how physical stress can act as a potent-and underappreciated- driver of epigenetic change.
This study was supported by the Ludwig Institute for Cancer Research, National Cancer Institute, the Cancer Research Society, the Canadian Institutes of Health Research, the U.S. National Institutes of Health, the Melanoma Research Alliance, The Debra and Leon Black Family Foundation, the Pershing Square Sohn Foundation, The Mark Foundation, The Alan and Sandra Gerry Metastasis Research Initiative at MSKCC, The Harry J. Lloyd Foundation, Consano, the Starr Cancer Consortium and the American Cancer Society.
Richard White is a member of the Oxford Branch of the Ludwig Institute for Cancer Research and a professor of genetics at the University of Oxford, Nuffield Department of Medicine.
