How melanomas reach the brain – and how to stop them

How do 90 percent of advanced melanomas (skin cancer) penetrate the blood-brain barrier and metastasize to the brain?

That was the question that puzzled cancer biologist Prof. Ronit Satchi-Fainaro of Tel Aviv University.

“It’s a confusing statistic,” Satchi-Fainaro noted. “We expect metastases in the lungs and liver, but the brain is said to be a protected organ. The blood-brain barrier prevents pollutants from entering the brain, and this is where it supposedly fails — cancer cells from the skin circulate in the blood and make it to the brain. We asked ourselves ‘who’ are the cancer cells ‘talking to’ in the brain to introduce it.”

Satchi-Fainaro and PhD student Sabina Pozzi discovered that the cancer cells communicate with astrocytes, star-shaped cells in the spinal cord and brain that are responsible for maintaining stable states in the brain.

“The astrocytes are the first to correct the situation, for example in the event of a stroke or trauma,” said Satchi-Fainaro, “and with them the cancer cells interact, exchange molecules and spoil them.”

When the astrocytes secrete a pro-inflammatory protein, the cancer cells begin to express receptors that Satchi-Fainaro says “we suspected were responsible for the destructive communication with the astrocytes.”

To test this hypothesis, the researchers inhibited the expression of this protein and cancer cell receptors in genetically engineered laboratory models and 3D models of melanoma and brain metastases.

They used an antibody (a biological molecule) and a synthetic molecule designed to block the attacking protein. They also used CRISPR technology to genetically edit the cancer cells, cutting out the two genes that express the corresponding receptors.

The result: The researchers were able to delay the spread of the metastases by up to 80%.

Doctoral student Sabina Pozzi, left, and Prof. Ronit Satchi-Fainaro. Photo courtesy of Tel Aviv University

Your research is crucial because melanoma metastases are particularly aggressive. The patients have a “poor prognosis 15 months after surgery, radiation and chemotherapy,” Satchi-Fainaro noted.

The treatment, when applied immediately after surgery, prevented the metastases from entering the brain. “I believe the treatment is clinically appropriate as a preventive measure,” Satchi-Fainaro said.

Best of all, the antibody and synthetic molecule have already been tested on humans and are believed to be safe. They are used to treat sclerosis, diabetes, liver fibrosis and cardiovascular diseases.

The research was conducted in collaboration with other scientists and physicians from Tel Aviv University, the US National Institutes of Health, Johns Hopkins University and the University of Lisbon.

The study published in the scientific journal JCI insightwas funded by the European Research Council, the Melanoma Research Alliance, the Kahn Foundation, the Israel Cancer Research Fund and the Israel Science Foundation.

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