Skin cancer cells produce “molecular drills” to penetrate healthy tissues and spread around the body, according to research that raises the prospect of new therapies for the disease.
Researchers used robotic microscopy to capture the formation of the drills by melanoma cells that were being grown in 3D skin-like material in the laboratory.
The drills help tumour cells to attach and punch holes in surrounding cells and structures, allowing the cancer to move beyond the site where it forms and reach into other tissues and organs.
“This is the first time this type of cell shape change has been associated with any type of metastatic cancer,” said Chris Bakal, professor of cancer morphodynamics at the Institute of Cancer Research in London.
Rates of melanoma have more than doubled in the UK since the 1990s, with more than 16,000 people newly diagnosed with the disease each year. In the early stages, tumours can often be removed by surgeons, but the cancer becomes more difficult to treat as it spreads to other parts of the body.
Bakal and his colleagues grew melanoma cells in a 3D matrix rich in collagen, one of the main proteins found in skin. By depleting genes in the cancer cells one by one, they discovered a particular gene, ARHGEF9, which was crucial to the formation of the molecular drills.
The gene is found in all human cells, but in adults it tends only to be turned on in brain cells to help them make new connections. Much earlier in human development, the gene allows neurons to produce their own drill-like structures, which help the cells to spread through the body and wire up the nervous system.
Writing in the journal iScience, the researchers describe how disabling the ARHGEF9 gene in melanoma cells destabilised the molecular drills so the cancer could no longer attach and bore into neighbouring tissues.
The finding raises hopes of new therapies for melanoma and possibly other cancers, such as neuroblastoma, that may spread in the same way. Although mutations in the ARHGEF9 gene are linked to a wide range of neurological disorders, the gene is thought to be more important during early development than in adulthood. If that is the case, developing drugs to inhibit the gene might block the spread of melanoma without serious side-effects.
“We feel that disarming the drill is likely to have widespread application,” said Bakal, though he suspects the process will not be relevant for all melanomas. Because the gene is highly active in metastatic cells, and less so in many other normal cells, drugs that target it might be more selective to cancer cells and so less toxic, he added.
Beyond paving the way for future treatments, the work may have much broader implications for understanding cancer. “This work could ultimately change how we think about cancer cells and tumours. Specifically, neurons interact in large networks to form brains, talk via neurotransmitters, and propagate information through electricity,” said Bakal.
“Our work is showing that many cancer cells may act similarly to form these networks and that tumours might almost be ‘brain-like’. The drills or sensors we identified here could be one way that cancer cells plug into this network and relay information to each other.” Further work in the lab suggests cancer cells are electrically highly active.
Dr Sam Godfrey at Cancer Research UK said the results were encouraging. “These findings will allow future research to focus on the role of this target in melanoma, and whether it could also help us beat certain cancers affecting children and young people,” he said. “Understanding more about the biology of this disease will lead to new tests and treatments for people with melanoma.”
