Using black-and-white-striped zebrafish to model human melanoma, they showed that a specific mutation in a gene called BRAF is critical to the development of moles, and when combined with a separate mutation, leads to cancer. Their findings appear in the February 8th issue of Current Biology.
Melanoma is now an epidemic cancer: its incidence is rising faster than that of any other cancer, doubling every 10-20 years. When melanoma is metastatic, or spreads to other organs, the average life expectancy is only 6-10 months. Previous studies have indicated that the BRAF gene is mutated in about 75 percent of melanomas, but until this study, no one knew its role, if any, in causing the cancer.
Dr. Leonard Zon, a Howard Hughes Medical Institute investigator in the Children's/Dana-Farber Division of Hematology/Oncology, postdoctoral fellow Dr. Elizabeth Patton, and colleagues genetically engineered zebrafish to make the mutated form of human BRAF. The mutant fish developed black-pigmented moles on their skin, but none developed melanoma. When the fish were also made to be deficient for a gene called p53, which suppresses tumor growth, the moles developed into invasive melanomas resembling human cancers. When cells from these tumors were injected into healthy zebrafish, they too developed melanomas.
"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, like a deficiency in the p53 tumor suppressor gene, to get melanoma."
Other animal models of melanoma exist, but the zebrafish is an exceptionally good one: its genome is very similar to the human genome and has been fully sequenced, so all its genes are known. The zebrafish is also very easy to study -- females have 300 babies a week, allowing scientists to very quickly create genetic variations and see the results. In fact, tumors are readily visible in zebrafish, allowing researchers to watch them progress. The fish can also be made to display the effects of gene mutations visually through genetic tricks that make the affected cells and tissues fluoresce. "The visual nature of the fish makes it an attractive model for studying cancer," adds Zon. "We can track a cancer and follow the fate of individual cells as the tumor grows and spreads." Now that the zebrafish model has been created, Zon's team will use it to examine how melanomas metastasize, and to look for other gene mutations besides the p53 mutation that participate in transforming moles into malignant melanomas.
"Some of these genes may lead us to excellent pharmaceutical targets for treatment of melanomas," Zon says.
Once these targets are identified, the zebrafish can be used to test potential anti-melanoma drugs that hit the targets. Researchers will also be able to test the effects of risk factors for human melanoma, such as exposure to ultraviolet radiation, and how they interact with gene mutations to cause disease.
Finally, Zon, who also directs the Children's Hospital Boston Stem Cell Program, will use the fish to learn more about cancer stem cells. Most tumor cells, when transplanted, can't give rise to a new cancer because they lack the capacity to divide and multiply. But tumors often have a subgroup of cells that can self-renew, as stem cells do, and create a new cancer -- as seen in these melanoma experiments. Studying these cells may turn up genes involved in metastasis, for example. "We're hoping to look at cancer as a stem cell problem," says Zon.