Melanoma skin cancer is among the quickest-spreading cancer types. Nearly all UK individuals with melanoma survive cancer for a year or longer if detected early before it spreads. However, once the disease has spread, the survival rate falls slightly over 50%.
A new study aims to equip with the knowledge to treat melanoma and unlock an improved understanding of how all cancers spread. The study, led by investigators at Queen Mary University of London, suggests that melanoma skin cancer cells radically rewire their internal power systems to drive their spread to other parts of the body. Reversing this change can make tumor cells less invasive.
The scientists also discovered an important molecule that controls this process; this information could serve as the basis for brand-new treatment approaches to stop the spread of cancer.
The group looked into how metastasizing cells reorganize their energy systems to travel fast and effectively to other places in the body.
The scientists used a unique model system that allowed for movement in three dimensions- a departure from conventional systems that place cells on flat surfaces that don’t accurately replicate how cells move through living tissue. They discovered that metastasizing tumor cells move in a way called rounded-amoeboid migration, which allows the cells to maintain a loose link to their surroundings and slither through the tissue. This requires much less energy than the typical mesenchymal migration, in which cells cling tenaciously to their environment and drag themselves through it.
They saw that the invasive tumor cells changed the configuration of their mitochondria to accommodate this practical kind of mobility, choosing to have numerous, little, fragmented mitochondria that function in a low-power mode. Less intrusive cells, in contrast, have extensive, branching networks of mitochondria that function in a high-power mode.
Dr. Eva Crosas-Molist, the first author of the new paper, said, “These metastatic cells are rewiring themselves to be very efficient. They only need low levels of energy to move, which helps them to survive in the potentially stressful environments they are migrating to, where there may be a lack of nutrients or oxygen.”
Interestingly, the team discovered that the metastasizing tumor cells lose their invasive behavior if the mitochondria’s structure is altered and forced to become more joined together. Likewise, non-invasive cells act like cancer cells spreading when their mitochondria are made more disjointed. The scientists found that the key player in these processes is a molecule known as AMPK. It recognizes the cell’s energy needs and regulates the cytoskeleton, which affects how the cell moves and functions.
Professor Sanz-Moreno explains, “That was a really surprising thing for us – we wouldn’t have imagined that changing the mitochondria could affect the cytoskeleton and vice versa.”
“By modifying these little mitochondria, you create a global change, altering what the cell looks like and its whole behavior.”
- Graziani, V., Maiques, O., Pandya, P., Monger, J., Samain, R., George, S. L., Malik, S., Salise, J., Morales, V., Le Guennec, A., Atkinson, R. A., Marti, R. M., Charras, G., Conte, M. R., & Holt, M. (2023). AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration. Nature Communications, 14(1), 1-22. DOI: 10.1038/s41467-023-38292-0