| 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. Copyright © 2016, American Association for the Advancement of Science. |
| Keywords: |
genetics; mutation; animal; metabolism; animals; melanoma; skin neoplasms; melanocyte; melanocytes; embryonic stem cell; green fluorescent protein; nerve tissue proteins; protein p53; carcinogenesis; transgenic animal; gene expression regulation; gene expression regulation, developmental; gene expression regulation, neoplastic; skin tumor; experimental melanoma; melanoma, experimental; reporter gene; tumor suppressor protein p53; embryonic stem cells; green fluorescent proteins; genes, reporter; neural crest; nerve protein; b raf kinase; zebra fish; zebrafish; proto-oncogene proteins b-raf; braf protein, human; transcription factor sox; enhancer region; enhancer elements, genetic; enhanced green fluorescent protein; animals, genetically modified; zebrafish proteins; zebrafish protein; soxe transcription factors; crestin protein, zebrafish; sox10 protein, zebrafish
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