Unveiling a Hidden Power Source in Cancer Cells
A groundbreaking study from the Centre for Genomic Regulation (CRG) in Barcelona reveals that cancer cells possess a rapid, localized energy boost when they are squeezed through tight spaces. In experiments using a specialized microscope that compresses living cells to three microns wide, researchers observed a dramatic, immediate rally of mitochondria to the nucleus, pumping in ATP — the cellular energy currency — at a rate that helps cancer cells survive mechanical gauntlets during invasion.
Key observations centered on HeLa cells, a widely used cancer line. Within seconds of confinement, mitochondria formed a tight halo around the nucleus, an arrangement the team named nucleus-associated mitochondria, or NAMs. This PERINUCLEAR battery of energy appeared in 84 percent of confined cancer cells, a stark contrast to virtually none in floating, uncompressed cells. The halo even caused the nucleus to dimple inward, signaling a robust structural and energetic response to physical stress.
The team used a fluorescent sensor to track ATP movement. When cells were squeezed, the sensor lit up, showing a roughly 60 percent increase in ATP entering the nucleus within three seconds. “It forces us to rethink the role of mitochondria in the human body. They aren’t static batteries powering our cells, but agile first responders summoned in emergency situations when cells are pressed to the limit,” said Dr. Sara Sdelci, co-corresponding author. This rapid ATP surge indicates a dynamic metabolic rewiring in the face of mechanical pressure.
More than just an energy spike, NAMs appear to be a strategic tool for maintaining genome integrity under stress. DNA inside squeezed cells is prone to damage as mechanical forces twist and snap strands. Cells rely on ATP-driven repair crews to loosen DNA and reach damaged sites for repair. In the experiments, squeezed cells that received the extra ATP repaired DNA within hours, while those without such an ATP boost lagged in recovery and failed to divide properly.
The biological significance of NAMs extended beyond the lab. When the researchers examined breast tumor biopsies from 17 patients, NAM halos were detected in 5.4 percent of nuclei at invasive tumor fronts, compared with 1.8 percent in the dense tumor core. This three-fold difference suggests NAMs may play a role in invasion and metastasis in real-world tumors. “Seeing this signature in patient biopsies convinced us of the relevance beyond the lab bench,” said Dr. Ritobrata (Rito) Ghose, co-first author of the study.
What Builds the NAM Halo?
The study also traced the cellular architecture enabling NAM formation. Actin filaments, the same protein networks that allow muscle contraction, wrap around the nucleus. The endoplasmic reticulum forms a mesh-like net, and together these structures physically trap NAMs into a halo around the nucleus. Disrupting the actin scaffold with latrunculin A dismantled NAMs and reduced the ATP surge, underscoring the mechanical basis of this metabolic adaptation.
Implications for Therapy
If metastatic cancer cells depend on NAM-driven ATP surges to survive mechanical stress and repair DNA, then targeting the NAM scaffolding could blunt invasiveness without broadly harming mitochondria in healthy cells. Researchers propose that blocking the actin-nuclear interface or other components of the NAM halo may render tumors less able to traverse tissue barriers, potentially limiting metastasis while sparing normal tissues.
“Mechanical stress responses are an underexplored vulnerability of cancer cells that can open new therapeutic avenues,” commented Dr. Verena Ruprecht, co-corresponding author. The discovery invites a broader view of cancer biology, suggesting that similar energy-boosting strategies could operate in immune cells, neurons, and developing tissues when physical forces are at play.
A New Layer in Cell Biology
As the authors emphasize, NAMs could represent a universal cellular strategy to safeguard genome integrity under pressure. “Wherever cells are under pressure, a nuclear energy boost is likely safeguarding the integrity of the genome,” concluded Dr. Sdelci. The finding marks a fundamental shift in how scientists understand mitochondrial dynamics and cellular resilience, with potential ripple effects across cancer biology and beyond.
