A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation

Charles K. Kaufman, Christian Mosimann, Zi Peng Fan, Song Yang, Andrew J. Thomas, Julien Ablain, Justin L. Tan, Rachel D. Fogley, Ellen Van Rooijen, Elliott J. Hagedorn, Christie Ciarlo, Richard M. White, Dominick A. Matos, Ann Christin Puller, Cristina Santoriello, Eric C. Liao, Richard A. Young, Leonard I. Zon

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

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 BRAFV600E 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 (BRAFV600E -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.

Original languageEnglish
Pages (from-to)464 and aad21971-aad219710
JournalScience
Volume351
Issue number6272
DOIs
StatePublished - Jan 29 2016

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