The early detection of a cancer can be crucial for its successful treatment. In the case of melanoma, the stage at diagnosis can mean the difference between simple, minimally invasive excision, and more intensive treatment involving radiation and/or chemotherapy. According to the American Cancer Society, 5-year survival rates for melanoma exceed 90% if intervention occurs at the earliest stages, but can drop as low as 15% if it has grown untreated and metastasized to other tissues.
Approximately 80% of human moles carry a mutation to the Braf gene. This gene encodes a protein involved in signaling pathways for normal cell proliferation and differentiation during embryonic development, but is also classified as an oncogene for its potential to induce tumor growth when mutated. Despite the frequency of Braf mutations in moles, very few become cancerous. What drives those that do?
Charles Kaufman and his colleagues are illuminating the processes behind melanoma initiation and development using a zebrafish melanoma model (Science 351, 6272; 2016). Melanoma originates from melanocytes, pigmentation cells derived from embryonic neural crest cells. The study visualized early melanoma in zebrafish carrying a Braf mutation by attaching a fluorescent protein to the gene crestin, found in embryonic neural crest progenitors and in adult melanoma. Their technique allowed the researchers to detect the expression of crestin before tumors became visible on the scales of the fish. All thirty cells observed with fluorescent crestin developed into melanoma over the course of the study.
The team continued their research with an investigation of potential melanoma regulators. They manipulated the expression of sox10, a gene involved in regulating crestin during embryonic development that has also been documented in melanoma. By increasing the expression of sox10, they found that melanoma development accelerated, while inactivating the gene with CRISPR/Cas9 slowed the onset of tumors. These results support their conclusion that the reemergence of neural crest progenitors is closely involved with triggering malignancy and suggest that disease development could potentially be influenced by modifying regulatory genes.
Kaufman and his team's fluorescent zebrafish model enabled them to visualize melanoma before the appearance of visible tumors and follow its progression from a single cell, providing evidence that neural crest progenitor reemergence is an important element involved in initiating malignancy in otherwise benign moles containing Braf gene mutations. The model and results should be valuable in future efforts to discern suspicious moles at the earliest stages.
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Neff, E. Illuminating melanoma at the molecular level. Lab Anim 45, 318 (2016). https://doi.org/10.1038/laban.1097