Melanoma Metastasis Discovery: Skin Cancer Rewires Energy Systems to Spread

AMPK senses the energy requirements of the cell and also controls the cytoskeleton, which determines how the cell moves and behaves.

Melanoma skin cancer cells may rewire their internal power systems to drive their spread to other parts of the body, a new study suggests.

The research, led by investigators at Barts Cancer Institute, Queen Mary University of London, suggests that reversing this change can make tumor cells less invasive. The team also identified a key molecule that orchestrates this process, which could lay the foundations for new therapeutic strategies to halt the spread of cancer.

Cancer cells’ ability to break away from the original tumor and spread to other parts of the body presents one of the greatest challenges to treating the disease. This process, called metastasis, seeds secondary tumors that grow in other organs, ultimately causing most cancer deaths.

“We’re still not targeting the secondary disease enough in the clinic, and I think we need to change this,” says Professor Victoria Sanz-Moreno, lead author of the new study, in a news release. “In our lab, we want to understand: what are the characteristics of cells that are able to metastasize? What are their weaknesses? And how do we target them?”

In the new study, published in Nature Communications, the team investigated how metastasizing cells rewire their energy systems to move quickly and efficiently on their journey to other parts of the body. ­

The researchers examined migrating tumor cells in a special model system allowing movement in three dimensions – a departure from conventional systems that place cells on a flat surface that doesn’t accurately replicate how cells move through living tissue. They found that metastasizing tumor cells adopt a style of movement known as rounded-amoeboid migration, where cells maintain a loose connection to their surroundings, enabling them to slither through the tissue. This requires far less energy than a common style of cell movement known as mesenchymal migration, where cells grip tightly onto their surroundings and drag themselves through their environment.

They observed that the invasive tumour cells reshape their mitochondria to suit this efficient style of movement, opting to have many, small, fragmented mitochondria that operate in a low-power mode. This is in contrast to less-invasive cells, which have large, branching networks of mitochondria that operate in a high-power mode.

“These metastatic cells are rewiring themselves to be very efficient,” explains study author Dr Eva Crosas-Molist. “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.”

The team found that if they manipulate the shape of the mitochondria in their metastasizing tumor cells and force them to become more joined up, the cells lose their invasive behavior. Likewise, if they make mitochondria more disconnected in non-invasive cells, the cells start to behave like metastasizing tumor cells. The researchers discovered that a molecule called AMPK sits at the center of these processes. It senses the energy requirements of the cell and also controls the cytoskeleton, which determines how the cell moves and behaves.

“That was a really surprising thing for us – we wouldn’t have imagined that changing the mitochondria could affect the cytoskeleton and vice versa.” Professor Sanz-Moreno explains. “By modifying these little mitochondria, you create a global change, altering what the cell looks like and its whole behavior.”

Professor Ketan Patel, Chief Scientist at Cancer Research UK, adds: “Patients whose cancer has spread often face tougher treatments and lower chances of survival. These insights about how cancer cells travel around the body could be incredibly valuable for designing interventions to prevent this in the future. The more we know about what’s happening in the bodies of people with cancer, the greater our ability to tackle it will be.”

The work was supported by Cancer Research UK; Barts Charity; Fundación Ramón Areces  and World Wide Cancer Research.