Tejal Somvanshi
Physical pressure inside tumors can force cancer cells to dramatically change their behavior, according to new research published in Nature. When squeezed into tight spaces, melanoma cells switch from rapid growth to a more invasive, drug-resistant state.
The study, conducted by researchers from Memorial Sloan Kettering Cancer Center and Ludwig Oxford, used zebrafish with melanoma to observe how cancer cells respond to physical confinement. They found that instead of continuing to multiply quickly, confined cancer cells activate what’s called a “neuronal invasion program” that helps them spread into surrounding tissues.
“Cancer cells can rapidly switch between different states, depending on cues within their environment,” explains Professor Richard White, who led the research. “Our study has shown that this switch can be triggered by mechanical forces within the tumor microenvironment.”
A protein called HMGB2 plays a key role in this transformation. When cancer cells feel the squeeze, HMGB2 binds to chromatin—the material that packages DNA—and changes how genetic material is organized. This exposes parts of the genome linked to invasiveness, making cells less focused on growth but more capable of invasion and resisting treatment.
The research team also discovered that melanoma cells create a protective cage-like structure around their nucleus when under pressure. This shield involves the LINC complex, a molecular bridge that connects the cell’s internal skeleton to the nuclear envelope, protecting the nucleus from damage caused by the stress of confinement.
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This finding reveals an important challenge for cancer treatment. Most current therapies target fast-growing cells, but they might miss cancer cells that have switched to this slower-growing but more invasive state due to physical pressure.
Unlike genetic mutations that permanently change DNA, these pressure-induced changes are epigenetic—they alter how genes are expressed without changing the DNA sequence itself. This means they could potentially be reversed with the right approach.
Traditional understanding of cancer cell changes has focused on internal chemical processes or signals in the tumor environment. This study adds physical pressure as another important factor that can flip the switch between different cancer cell behaviors.
The research suggests new treatment strategies might be possible. By targeting the way cancer cells respond to pressure or the protective mechanisms they use when confined, future treatments could potentially make tumors more vulnerable to existing therapies.
As scientists continue to study how tumors interact with their physical surroundings, this work opens new avenues for understanding and potentially treating aggressive cancers like melanoma, where invasion and treatment resistance remain major challenges.
The research, titled “Mechanical confinement governs phenotypic plasticity in melanoma,” was published in Nature on 28 August 2025.
