Pressure to Kill: How Squeezing Cancer Cells Makes Them Deadlier

New Research: Physical Pressure Triggers Cancer Cells to Turn Deadly

A landmark study published in Nature has uncovered a paradoxical trigger for cancer's most dangerous behavior: physical pressure. Conducted by researchers at the Ludwig Institute for Cancer Research and Memorial Sloan Kettering Cancer Center, the findings show that when cancer cells are mechanically squeezed inside a tumor, they don't die—they transform into more invasive, drug-resistant versions of themselves.

The Dangerous Switch: From Growth to Invasion

Using a zebrafish model of melanoma, the team discovered that confinement by surrounding tissues forces cancer cells to undergo a dramatic state change. Instead of continuing to proliferate, they activate a specific program known as 'neuronal invasion', which equips them to migrate and spread into new tissue—the fundamental driver of metastasis.

The Key Protein: HMGB2 Flips the Epigenetic Switch

At the heart of this transformation is a protein called HMGB2. The study demonstrates that HMGB2 acts as a mechanical sensor. When a cell is squeezed, HMGB2 binds directly to chromatin, the complex of DNA and protein, and alters its 3D structure. This epigenetic change does not mutate the DNA but instead exposes previously hidden genes linked to invasiveness, effectively reprogramming the cell for escape.

A Double Defense for Survival

The cells' adaptation goes beyond genetic reprogramming. To survive the physical stress, they also:

• Remodel their internal skeleton, forming a protective, cage-like structure around the nucleus.

• Utilize the LINC complex, a molecular bridge that shields the nucleus from rupture and DNA damage.

This dual mechanism ensures the cell not only becomes more aggressive but is also robust enough to survive the journey.

Major Implications for Cancer Treatment

This discovery reveals a significant challenge in cancer therapy. Treatments that target rapidly dividing cells may be ineffective against these dormant but invasive cells.

"As therapies targeting rapidly dividing cells may miss those that have transitioned to an invasive, drug-resistant phenotype, identifying the factors involved in this switch is crucial," explained senior author Richard White. "We hope to develop therapies that can prevent or even reverse this dangerous transformation."

By identifying HMGB2 and the physical forces of the tumor microenvironment as key drivers, this research opens a new frontier for developing treatments aimed at blocking cancer's ability to adapt and spread.