ZFIN ID: ZDB-PUB-180609-27
Neural crest state activation in NRAS driven melanoma, but not in NRAS-driven melanocyte expansion
McConnell, A.M., Mito, J.K., Ablain, J., Dang, M., Formichella, L., Fisher, D.E., Zon, L.I.
Date: 2018
Source: Developmental Biology   449(2): 107-114 (Journal)
Registered Authors: Zon, Leonard I.
Keywords: NRAS, Neural crest, cancer, melanoma
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Proliferation/genetics*
  • Disease Models, Animal
  • GTP Phosphohydrolases/genetics
  • GTP Phosphohydrolases/metabolism
  • Genes, ras/genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Melanocytes/metabolism*
  • Melanocytes/pathology
  • Melanoma/genetics*
  • Melanoma/metabolism
  • Melanoma/pathology
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Mutation*
  • Neural Crest/metabolism*
  • Skin Neoplasms/genetics*
  • Skin Neoplasms/metabolism
  • Skin Neoplasms/pathology
  • Time Factors
  • Zebrafish
PubMed: 29883661 Full text @ Dev. Biol.
NRAS mutations are frequently found in many deadly malignancies and are the second most common oncogene driving malignant melanoma. Here, we generate a rapid transient transgenic zebrafish model of NRASQ61R-mutant melanoma. These fish develop extensive melanocytic proliferation in approximately 4 weeks. The majority of these lesions do not engraft upon transplantation and lack overt histologic features of malignancy. Our previous work demonstrated that activation of a neural crest cell transcriptional program is a key initiating event in zebrafish BRAF/p53-driven melanomas using the fluorescent reporter crestin:EGFP. By 8-12 weeks of age, some lesions progress to malignant melanoma and have cytologic atypia, destructive tissue invasion, and express neural crest progenitor markers, including crestin:EGFP. Our studies demonstrate that NRASQ61R induces extensive melanocyte expansion, which arise during zebrafish development and lack a transformed phenotype. These early lesions are highly predisposed to reactivate a neural crest progenitor fate and form malignant melanomas.