How Cells Survive Intense Periods of Physical Stress

A recent study published in Nature Communications reveals that cancer cells immediately generate an energy surge when mechanically squeezed. This response enables them to survive and repair DNA damage when navigating crowded or confined environments within the body, like the tumor microenvironment. The study was conducted by scientists at the Centre for Genomic Regulation using quantitative live cell microscopy.

When cancer cells, specifically HeLa cells, were compressed, researchers observed that their mitochondria quickly moved to the surface of the cell nucleus. These mitochondria supplied extra ATP, the cell’s main energy molecule, directly to the nucleus. This created a tight “halo” of mitochondria—called NAMs for nucleus-associated mitochondria—so dense that it caused the nucleus to bend inward. This NAM structure formed in 84% of confined cells, yet was nearly nonexistent in uncompressed and free-floating cells. 

To determine the function of this phenomenon, the team used a fluorescent sensor to track ATP flow into the nucleus. They found a 60% surge in nuclear ATP within three seconds of compression. "It’s a clear sign the cells are adapting to the strain and rewiring their metabolism,” says Fabio Pezzano, co-first author of the study.

Further experiments demonstrated the importance of this energy for DNA repair. Physical squeezing induces stress and breaks in DNA. These require ATP for cellular repair machinery to access and mend the DNA strands. Cells that received the ATP surge resumed normal division after repairs, while those lacking the extra energy ceased dividing properly. 

The team also analyzed breast tumor biopsies from 17 patients, discovering that NAM halos were three times more common at invasive tumor edges than in the dense tumor core. “Seeing this signature in patient biopsies convinced us of the relevance beyond the lab bench,” explains Ritobrata Ghose, a co-first author. 

Investigation into the underlying mechanics showed that actin filaments and the endoplasmic reticulum form a scaffold around the nucleus, trapping mitochondria in position. Disrupting actin filaments with a drug called latrunculin A collapsed this structure and blocked the ATP flow.

If metastatic cells depend on NAM-driven ATP surges, drugs that block the scaffold could make tumours less invasive without broadly poisoning mitochondria and sparing healthy tissues. “Mechanical stress responses are an underexplored vulnerability of cancer cells that can open new therapeutic avenues,” says Verena Ruprecht, co-corresponding author.