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


Kaufman, C K; Mosimann, C; Fan, Z P; 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; Young, R A; Zon, L I (2016). A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science, 351(6272):aad2197.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:29 January 2016
Deposited On:12 Jan 2017 11:24
Last Modified:12 Jan 2017 11:48
Publisher:American Association for the Advancement of Science
ISSN:0036-8075
Additional Information:This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Science. 2016 Jan 29; 351(6272): aad2197. https://doi.org/10.1126/science.aad2197.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1126/science.aad2197
PubMed ID:26823433

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