A Zebrafish Melanoma Model Reveals Emergence of Neural Crest Identity During Melanoma Initiation

Science. 2016 Jan 29;351(6272):aad2197. doi: 10.1126/science.aad2197. Epub 2016 Jan 28.

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 BRAF(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(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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Carcinogenesis / genetics*
  • Embryonic Stem Cells / metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Developmental*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma, Experimental / genetics*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Neural Crest / metabolism*
  • Proto-Oncogene Proteins B-raf / genetics
  • SOXE Transcription Factors / genetics
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish*

Substances

  • Nerve Tissue Proteins
  • SOXE Transcription Factors
  • Tumor Suppressor Protein p53
  • Zebrafish Proteins
  • crestin protein, zebrafish
  • enhanced green fluorescent protein
  • sox10 protein, zebrafish
  • Green Fluorescent Proteins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Associated data

  • GEO/GSE75356