Melanoma is the deadliest kind of skin cancer. If diagnosed and treated by surgery, it is almost always curable – but if not, the malignancy can spread (metastasize) to other parts of the body where it becomes difficult to treat and is often fatal. 

The metastatic stage has a 10-year survival rate of less than 10% and a life expectancy of just two to seven months, depending on the number of organs to which the cancer has spread. This type of skin cancer spreads to the lymph nodes, lungs, liver, bones and brain. In most cases, melanoma is caused by exposure to ultraviolet (UV) radiation from the sun or tanning beds. It damages the DNA of the skin cells, and then they start to grow out of control.

But now, researchers at Tel Aviv University (TAU) have published in the journal Cell Reports that tumor cells “hijack” their way to the brain through an inflammatory factor secreted by brain cells. Following the discovery, the researchers were able to develop a method for neutralizing the mechanism, which may in the future block the pathway and prevent brain metastasis in melanoma patients. The accomplishment was performed in lab mice and found to work in tumor cells surgically removed from human brains. 

“The prognosis of patients with brain metastases is very grim,” said lead author Prof. Neta Erez of the pathology department at the university’s Sackler Faculty of Medicine. The research was conducted by TAU graduate students Dr. Hila Doron and Malak Amer, in collaboration with Prof. Ronit Satchi-Fainaro, also of the Sackler Faculty of Medicine. 

“Patients used to die from metastases in other places before brain metastases were clinically evident. Treatments have improved and patients are living longer, so the incidence of diagnosed brain metastases is increasing. Understanding how and why brain metastasis occurs is an urgent challenge facing cancer researchers today,” said Erez. “The new research focuses on melanoma brain metastasis because melanoma is the deadliest skin cancer due to its high rate of metastasis, frequently to the brain.” 

The Israeli scientists used a mouse model of spontaneous melanoma- brain metastasis to study the interactions of melanoma tumors within the brain microenvironment. They discovered that melanoma brain metastasis is made possible by the takeover of a physiological inflammatory pathway by astrocytes, the brain cells that maintain a protected environment in the brain. The astrocytes also respond to tissue damage in the brain by instigating an inflammatory and tissue repair response to contain the damage, secreting inflammatory factors that recruit immune cells. 

“We discovered that tumor cells recruit these inflammatory factors to hijack their way to the brain,” explained Erez. “We identified a specific factor that mediates their attraction to the brain and showed that brain metastasizing melanoma cells express the receptor for the inflammatory factor, which is how they respond to this signal.”

Significantly, when the researchers used genetic tools to inhibit the expression of the receptor on melanoma cells, they successfully blocked the ability of tumor cells to respond to astrocyte signaling — and the development of brain metastases was significantly inhibited.

After the initial research was performed in a mouse model, the scientists validated their results in the brain metastases of patients who had undergone brain surgery, finding that astrocytes express the same inflammatory factor (CXCL10) and that the tumor cells express the same receptor (CXCR3) as the mouse model. This suggests that the identical mechanism is operative in humans.

“Our findings suggest that blocking this signaling pathway may prevent brain metastasis,” concluded Erez. “The CXCL10-CXCR3 axis may be a potential therapeutic target for prevention of melanoma brain metastasis.” The researchers are currently investigating the trigger that instigates inflammation in the brain, which promotes metastasis.