According to a new study, melanoma skin cancer cells fundamentally
reorganise their internal power systems in order to move to other places of the body.
The research, led by investigators at Barts Cancer Institute, 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, which was funded
by Cancer Research UK. "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 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 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."
Professor Ketan Patel, Chief Scientist at Cancer Research UK, said " 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."
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