Skin cancer rewires its energy systems to spread more efficiently

Dr Eva Crosas-Molist

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

Cancer cells’ ability to break away from the original tumour and spread to other parts of the body presents one of the greatest challenges to treating the disease. This process, called metastasis, seeds secondary tumours 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,” comments Professor Victoria Sanz-Moreno, lead author of the new study based in Queen Mary’s Barts Cancer Institute. “In our lab, we want to understand: what are the characteristics of cells that are able to metastasise? What are their weaknesses? And how do we target them?” 

Melanoma skin cancer is among the quickest-spreading cancer types and is a key focus of Professor Sanz-Moreno and her laboratory’s research. If melanoma is diagnosed at an early stage before it spreads, almost all patients in the UK survive their disease for a year or more. But this survival drops to just over half once the disease has spread. The team’s work aims not only to equip us with the knowledge to better treat melanoma but also to unlock an improved understanding of how all cancers spread. 

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

The researchers examined migrating tumour 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 metastasising tumour 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 contrasts with 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 Dr Eva Crosas-Molist, first author on the new paper. “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.” 

Intriguingly, the team found that if they manipulate the shape of the mitochondria in their metastasising tumour cells and force them to become more joined up, the cells lose their invasive behaviour. Likewise, if they make mitochondria more disconnected in non-invasive cells, the cells start to behave like metastasising tumour cells. The researchers discovered that a molecule called AMPK sits at the centre 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 behaviour.”