Boston Children's team finds potential new melanoma drug target using zebrafish

Illustration showing crestin activation in a zebrafish melanocyte--Screenshot courtesy of Boston Children's Hospital

Why some cancer-prone cells don't ever cross the line into actually becoming malignant is a mystery that has long eluded scientists. Now, researchers at Boston Children's Hospital have answered that question, at least for melanoma. And in doing so, the team visualized for the first time the spread of cancer from a single cell and identified a set of genes as a potential new drug target.

The researchers studied zebrafish that had a cancer mutation commonly found in benign moles and had also lost the tumor suppressor gene p53. But these cancer-predisposed fish only developed cancer if a specific set of genes in a cancer-prone cell was activated. So, the team engineered the fishes' cells to light up fluorescent green if the gene crestin was activated, the signal that this set of genes was switched on.

"Every so often we would see a green spot on a fish," said Dr. Leonard Zon, director of the Stem Cell Research Program at Boston Children's and senior investigator on the study which was published in Science, in a statement. "When we followed them, they became tumors 100 percent of the time."

These genes cause melanocytes (skin pigment cells) to revert back to a primitive "neural crest" state and behave like stem cells, the researchers found. Unchecked, cells in this primitive state are able to proliferate, spreading cancer. This group of genes is switched on in human melanomas and in zebrafish embryos. They switch off, terminating the stem-cell program once embryonic development is over. Why they switch back on later in life is still a mystery.

While skin cancer is the most common of cancers, melanoma is rare, accounting for 1% of all skin cancers, according to the American Cancer Society. However, the 5-year survival rates for melanoma decrease sharply as the cancer worsens, going from the 92% to 97% in stage I melanoma to between 15% and 20% in stage IV melanoma.

The DNA elements that are responsible for switching on this stem cell program could represent a potential new drug target to stop melanoma before it even develops. Zon and his team envision a new diagnostic test to diagnose a suspicious mole as malignant. In 2013, Cornell University researchers found the source of stem cell-like cells that caused ovarian cancer in mice. However, they just found the source of cancer-predisposed cells, not the mechanism by which they become truly cancerous.

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