Stress from surrounding tissues prompts invasive applications in most cancers cells. This mechanical stress rewires epigenetic regulation.
Most cancers cells are notoriously adaptable, able to shifting their traits as they unfold all through the physique. Many of those shifts stem from epigenetic modifications, which affect 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.
Mechanical stress and HMGB2
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.
Remodeling under pressure
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 be 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.
Reference: “Mechanical confinement governs phenotypic plasticity in melanoma” by Miranda V. Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P. Koche and Richard M. White, 27 August 2025, Nature.
DOI: 10.1038/s41586-025-09445-6
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.
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