About 60,000 Americans will be diagnosed with melanoma this year, says the American Cancer Society, and 10,000 of those cases will be fatal. If not caught in the early stages, melanoma can be a particularly virulent form of cancer, spreading through the body with an efficiency that few tumors possess.
Now, a team led by researchers at MIT and the Whitehead Institute for Biomedical Research has discovered one of the reasons why this particular skin tumor is so ruthless. Unlike other cancers, melanoma is born with its metastatic engines fully revved.
"Other cancers need to learn how to spread, but not melanoma," says Whitehead Member Robert Weinberg, an MIT professor of biology and senior author of a paper on the work in the journal Nature Genetics. "Now, for the first time, we understand the genetic mechanism responsible for this."
Metastasis (the spread of disease to another body part) is a highly inefficient, multistep process that requires cancer cells to jump through many hoops. The cells first must invade a nearby tissue, then make their way into the blood or lymphatic vessels. Next they must migrate through the bloodstream to a distant site, exit the bloodstream and establish new colonies.
Researchers have wondered why melanoma in particular is able to do this not only more efficiently than other cancers, but at a far earlier stage. This new study shows that as melanocytes -- cells that protect the skin from sun damage by producing pigmentation -- morph into cancer cells, they immediately awaken a dormant cellular process that lets them travel swiftly throughout the body.
Central to this reawakening process is a gene called Slug (named after the bizarre embryo shape that its mutated form can cause in fruit flies). Slug is active in the neural crest, an early embryonic cluster of cells that eventually gives rise to a variety of cell types in the adult, including dermal melanocytes. In this early embryonic stage, Slug enables the neural crest cells to travel and then settle throughout the developing embryo.
"Slug is a key component of the neural crest's ability to migrate," says Piyush Gupta, a MIT graduate student in Weinberg's lab and first author on the paper. "Following its activation during embryonic development, Slug is shut off in adult tissues." But when skin cells in, say, an individual's mole, become malignant, they readily reactivate Slug and gain the ability to spread -- something that other cancers can spend decades trying to do.
The research team found that when Slug was knocked out in melanoma cells, the cancer was unable to metastasize when placed into a mouse.
"This work is yet another demonstration of the notion that certain embryonic genes normally involved in transferring cells from one part of the body to another are also involved in enabling cancer cells to spread," says Weinberg.
Additional authors of the paper are from Tufts University, New England Medical Center, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Harvard University and the University of California at San Francisco.
This research was supported by the National Institutes of Health and the National Cancer Institute.
