A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation
Author(s)Kaufman, C. K.; Mosimann, C.; Yang, S.; Thomas, A. J.; Ablain, J.; Tan, J. L.; Fogley, R. D.; van Rooijen, E.; Hagedorn, E. J.; Ciarlo, C.; White, R. M.; Matos, D. A.; Puller, A.-C.; Santoriello, C.; Liao, E. C.; Zon, L. I.; Young, Richard A; Fan, Zi Peng; ... Show more Show less
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The “cancerized field” concept posits that cancer-prone cells in a given tissue share an oncogenic mutation, but only discreet clones within the field initiate tumors. Most benign nevi carry oncogenic BRAF[superscript V600E] mutations but rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and specifically reexpressed in melanoma. Live imaging of transgenic zebrafish crestin reporters shows that within a cancerized field (BRAF[superscript V600E]-mutant; p53-deficient), a single melanocyte reactivates the NCP state, revealing a fate change at melanoma initiation in this model. NCP transcription factors, including sox10, regulate crestin expression. Forced sox10 overexpression in melanocytes accelerated melanoma formation, which is consistent with activation of NCP genes and super-enhancers leading to melanoma. Our work highlights NCP state reemergence as a key event in melanoma initiation.
DepartmentMassachusetts Institute of Technology. Computational and Systems Biology Program; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
American Association for the Advancement of Science (AAAS)
Kaufman, C. K. et al. “A Zebrafish Melanoma Model Reveals Emergence of Neural Crest Identity during Melanoma Initiation.” Science 351.6272 (2016): aad2197-aad2197.
Author's final manuscript