Cramped Space: The Mechanical Stress That Brings Out Cancer's Aggressive Side

Researchers have discovered that the physical environment surrounding a tumor, such as the tight space that compresses cells, can make cancer, especially melanoma, more aggressive. Instead of relying solely on DNA mutations, cancer cells change their behavior through the HMGB2 protein, which reorganizes chromatin (the way DNA is coiled). This causes them to stop multiplying and instead invade neighboring tissues, activating genes normally used by developing neurons. This discovery partly explains why some melanomas are so resistant to treatment and may open up new therapeutic strategies in the future.

Scientists already know that cancer cells can change their behavior without a new DNA mutation. This process is called cellular plasticity. In the case of melanoma, a type of skin cancer, this means that cells can alternate between two main states: one in which they multiply rapidly (a proliferative state) and another in which they move and invade other tissues (an invasive state).

This change depends not only on DNA but also on signals from the tumor's surrounding environment, known as the tumor microenvironment.

To better understand how this happens, researchers at Memorial Sloan Kettering Cancer Center in the USA used an experimental model with zebrafish genetically modified to develop melanoma, in addition to analyzing human tumor samples. Zebrafish were chosen because they are transparent animals in their early stages of life, which makes it easier to observe how the tumor grows and invades neighboring tissues, such as skin and muscle..

The scientists applied cutting-edge analysis techniques, such as spatial transcriptomics (which shows where genes are active within the tumor) and single-cell RNA sequencing (which allows the study of each cell's behavior individually).

They observed that, in the region where the tumor meets the surrounding healthy tissue, there is a special group of cells called interface cells. These cells show signs of being under physical pressure from the surrounding tissue, meaning they are compressed by the limited space.

When they compared them with data from melanoma patients, they discovered that these interface cells were also present in humans. They were more common in tumors that did not respond well to treatments like immunotherapy. This detail is important because it may explain why some melanomas are so resistant to drugs.

By studying the genes of these cells, the scientists noticed something curious: they turned off genes typical of skin cells (such as those responsible for pigment production) and began activating genes normally used by developing neurons. In addition, they formed a kind of “protective shell” around the nucleus, made of proteins such as tubulin, which helped the cells survive and move in tight spaces.

These images show melanoma cells in two situations: without pressure (unconfined) and under physical pressure (confined). The colors mark internal structures called microtubules, which function as the cell's "skeleton." Green shows acetylated microtubules, a more stable form of these fibers, and purple represents tubulin. When cells are squeezed by their environment, they produce many more of these stabilized microtubules, as if reinforcing their structure to resist and move in tight spaces. The graph confirms this: compressed cells have many more acetylated microtubules than uncompressed cells.

One of the key points of the research was the discovery of the role of a protein called HMGB2. This protein helps organize chromatin, the structure where DNA is coiled.

Under normal conditions, chromatin can be more open or more closed, which facilitates or hinders the activation of certain genes. When melanoma cells became compressed by surrounding tissue, HMGB2 was activated and changed the way chromatin was organized. As a result, the cells stopped multiplying as much but became more invasive and resistant to drugs.

This discovery shows that the physical environment surrounding the tumor, and not just genetic mutations, can strongly influence cancer behavior. In other words, simply having a tumor cell in a confined space can make it more aggressive.

The researchers concluded that melanoma can exploit mechanisms normally used by neurons during brain development, applying them to invade new tissue. This opens the way for new types of treatments, perhaps focused on blocking the action of the HMGB2 protein or modifying the mechanical forces of the tumor environment.

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Mechanical confinement governs phenotypic plasticity in melanoma

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

Nature. 27 August 2025. 

DOI: 10.1038/s41586-025-09445-6

Abstract: 

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.