Skin cancer adapts energy systems to increase proliferation

The study, led by researchers at Queen Mary University of London, suggests that removing this change could make cancer cells less invasive. The team also identified a key molecule orchestrating this process – knowledge that could lay the foundation for new therapeutic strategies to stop cancer from spreading.

The ability of cancer cells to break away from the primary tumor and spread to other parts of the body is one of the biggest challenges in treating the disease. This process, called metastasis, causes secondary tumors to grow in other organs, resulting in most cancer deaths.

“We’re still not targeting secondary disease well enough in the clinic and I think we need to change that,” says lead author of the new study, Professor Victoria Sanz-Moreno, based at Queen Mary’s Barts Cancer Institute. “In our laboratory, we want to understand: what are the characteristics of cells capable of metastasizing?” What are their weaknesses? And how do we target them?”

Melanoma skin cancer is one of the fastest growing types of cancer and is the focus of research for Professor Sanz-Moreno and his laboratory. If melanoma is diagnosed at an early stage before it has spread, almost all patients in the UK will survive their disease for a year or more. But once the disease spreads, that survival rate is only slightly cut in half. The team’s work aims not only to provide us with knowledge about better melanoma treatments, but also to reveal an improved understanding of how all cancers spread.

In a new study published in the journal 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 studied moving tumor cells in a special model system that allows for three-dimensional movement—a departure from conventional systems that place cells on a flat surface that doesn’t exactly replicate how cells move through living tissue. They found that metastasizing tumor cells adopt a style of movement known as circular amoeboid migration, where the cells are in loose contact with their environment, allowing them to slide through the tissue. This requires much less energy than the usual style of cell movement called mesenchymal migration, in which cells drag themselves through the environment in close contact with their environment.

They observed that invasive tumor cells alter their mitochondria to suit this efficient movement style, choosing to have many, small, fragmented mitochondria that operate in a low-power mode. This is in contrast to less invasive cells with large, branched networks of mitochondria operating in a high-energy mode.

“These metastatic cells regenerate themselves to be very efficient,” explains Dr. Eva Crozas-Molis, first author of the new paper. “They only need a low level of energy to move, which helps them survive in potentially stressful environments where they migrate, where there may be a lack of nutrients or oxygen.”

Interestingly, the team found that if they manipulated the shape of the mitochondria in metastasizing tumor cells, forcing them to fuse together, the cells lost their invasive behavior. Similarly, if they disassemble more mitochondria in non-invasive cells, the cells start to behave like metastasizing tumor cells. The researchers found that at the center of these processes is a molecule called AMPK. It senses the cell’s energy needs and also controls the cytoskeleton, which determines how the cell moves and acts.

“This was a surprise to us—we didn’t think that changing the mitochondria could affect the cytoskeleton and vice versa.” Professor Sanz-Moreno explains. “By changing these tiny mitochondria, you make a global change that changes the appearance of the cell and its entire behavior.”

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