Melanoma's origins swim into view
The zebrafish lab of Leonard Zon, MD, director of the Stem Cell/Develomental Biology Research Program, has again produced an important medical clue: using the tiny fish as a model, Zon and colleagues at Children's Hospital Boston and the Dana-Farber Cancer Institute have new insights into the genetic origins of the deadly skin cancer melanoma—the fastest growing cancer in terms of incidence, with rates doubling every 10 to 20 years.
Zon, a Howard Hughes Medical Institute investigator, and postdoctoral fellow Elizabeth Patton, PhD, showed that a specific mutation of a gene called BRAF is critical to the development of moles, which, when combined with a separate mutation, leads to cancer.
When Zon, Patton and colleagues genetically engineered zebrafish to make the mutated form of human BRAF, the fish developed black-pigmented moles on their skin, but none got melanoma. However, when the fish were also bred to be deficient in a tumor-suppressing gene called p53, the moles became invasive melanomas much like those in humans. And when cells from these tumors were injected into healthy zebrafish, they too developed melanomas. The team's findings appear in the February 8 issue of Current Biology.
"We now know that BRAF, when activated, is sufficient to make moles," says Zon. "We also know that it's insufficient to make cancer—you need other mutations to get melanoma."
Zebrafish make exceptionally good models for studying cancer: their genome is very similar to the human genome and all their genes are known. They're also easy to study: females have 300 babies a week, allowing scientists to quickly breed genetic variants and see the results. Tumors are readily visible in zebrafish, and the fish can be made to display the effects of gene mutations visually through genetic tricks that make the affected cells and tissues light up. "We can track a cancer and follow individual cells as the tumor grows and spreads," Zon says.
Zon's team is now looking at zebrafish to learn how melanomas metastasize; to study how risk factors for melanoma, like exposure to ultraviolet radiation, interact with gene mutations to cause disease; and to search for additional mutations that help transform harmless moles into malignant melanomas. "Some of these genes may lead us to excellent pharmaceutical targets for melanoma treatment," Zon says. The fish could then be used to test potential drugs that hit those targets.
Finally, Zon, who also directs Children's Stem Cell Program, will use zebrafish to learn more about cancer stem cells and their genetic attributes. Most tumor cells, when transplanted, don't give rise to a new cancer because they can't divide and multiply. But tumors often have individual cells that can reproduce themselves, just as stem cells do, and create a new cancer’Äîas seen in these melanoma experiments. "We're hoping to look at cancer as a stem cell problem," says Zon.
