A recent study led by researchers at Tel Aviv University (TAU) in Israel revealed the trigger that causes melanoma cells to transform into invasive, lethal cells. The study is entitled “Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF” and was published in the journal Molecular Cell.
Melanoma is the most dangerous form of skin cancer accounting for 2% of all cases and almost all skin cancer related deaths. Melanoma rates in the United States have been rapidly increasing in recent decades. Skin cancer is caused by damage to skin cells (usually by ultraviolet radiation from sunshine or tanning beds), which triggers mutations that are not repaired allowing cells to rapidly multiply and generate malignant tumors. Melanoma cancer can be removed when detected early, however, when the cancer invades the bloodstream potentially spreading throughout the body (metastatic form), treatment requires a more aggressive approach. It is not clear how melanoma cells transform into aggressive, invasive fatal forms.
Now researchers have discovered the precise trigger that makes melanoma cancer cells transform from non-invasive cells to invasive lethal agents.
“Melanoma is a cancer that originates in the epidermis, and in its aggressive form it will invade the dermis, a lower layer, where it eventually invades the bloodstream or lymph vessels, causing metastasis in other organs of the body. But before invading the dermis, melanoma cells surprisingly extend upward, then switch directions to invade.” explained the study’s senior author Dr. Carmit Levy in a news release. “It occurred to me that there had to be a trigger in the microenvironment of the skin that made the melanoma cells ‘invasive,’ (…) Using the evolutionary logic of the tumor, why spend the energy going up when you can just use your energy to go down and become malignant?”
The team collected samples from both normal skin cells and melanoma cells from patients in several hospitals in Israel and analyzed their gene expression profile to determine the cancer behavior in terms of migration.
Researchers found that, regardless of any mutation acquired, the microenvironment alone triggered melanoma metastasis. “Normal skin cells are not supposed to ‘travel,’” explained Dr. Levy. “We found that when melanoma is situated at the top layer, a trigger sends it down to the dermis and then further down to invade blood vessels. If we could stop it at the top layer, block it from invading the bloodstream, we could stop the progression of the cancer.”
More specifically, the team found that when melanoma cells have a direct contact with the remote epidermal layer, an invasion phenotype is triggered through the activation of a pathway known as Notch signaling, which induces a set of genes that ultimately results in a transformation of melanoma cells into invasive, lethal agents.
“When I saw the results, I jumped out of the room and shouted, ‘We got it!’” said Dr. Levy. “Now that we know the triggers of melanoma transformation and the kind of signalling that leads to that transformation, we know what to block. The trick was to solve the mystery, and we did. There are many drugs in existence that can block the Notch signalling responsible for that transformation. Maybe, in the future, people will be able to rub some substance on their skin as a prevention measure.”
Dr. Levy is also pursuing the development of a tool that could allow physicians to analyze different stages of melanoma, potentially reducing the number of deaths associated with this cancer. “Melanoma is a cancer with a very long gestation period, (…) If you can provide a simple kit with precise answers, you can catch it at the beginning stage and hopefully save lives.” concluded Dr. Levy.