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

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

Author information

1
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA.
2
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.
3
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA.
5
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
6
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA.
7
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA.
8
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10075, USA.
9
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
10
Research Institute Children's Cancer Center Hamburg and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
11
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
12
Harvard Stem Cell Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
13
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
14
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. zon@enders.tch.harvard.edu.

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.

PMID:
26823433
PMCID:
PMC4868069
DOI:
10.1126/science.aad2197
[Indexed for MEDLINE]
Free PMC Article

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