title: A zebrafish melanoma model reveals emergence of neural crest identity during 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 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.
authors.affiliation: 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.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Kaufman
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Mosimann
authors.affiliation: 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.
authors.forename: Zi Peng
authors.initials: ZP
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Ablain
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Tan
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Fogley
authors.affiliation: 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.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Rooijen
authors.affiliation: 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.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Hagedorn
authors.affiliation: 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.
authors.forename: Christie
authors.initials: C
authors.lastname: Ciarlo
authors.affiliation: Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10075, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: White
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Dominick A
authors.initials: DA
authors.lastname: Matos
authors.affiliation: Research Institute Children's Cancer Center Hamburg and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Puller
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Santoriello
authors.affiliation: 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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Liao
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: 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.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D063646:Carcinogenesis / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D008546:Melanoma, Experimental / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009432:Neural Crest / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D055757:SOXE Transcription Factors; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C407354:crestin protein, zebrafish; C485184:enhanced green fluorescent protein; C442229:sox10 protein, zebrafish; D049452:Green Fluorescent Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
references.citation: J Invest Dermatol. 2014 Aug;134(8):2212-2220
references.pmid: 24608986
references.citation: Nature. 2014 Jul 31;511(7511):543-50
references.pmid: 25079552
references.citation: Bioessays. 2006 Aug;28(8):788-98
references.pmid: 16927299
references.citation: Genome Res. 2009 Jul;19(7):1279-88
references.pmid: 19470664
references.citation: Dev Dyn. 2007 Nov;236(11):3077-87
references.pmid: 17948311
references.citation: Nature. 2011 Mar 24;471(7339):513-7
references.pmid: 21430779
references.citation: PLoS One. 2014 May 29;9(5):e98186
references.pmid: 24873830
references.citation: Nature. 2011 Mar 24;471(7339):518-22
references.pmid: 21430780
references.citation: Dev Biol. 2011 Dec 15;360(2):415-25
references.pmid: 22008794
references.citation: Nat Cell Biol. 2012 Dec;14(12):1282-94
references.pmid: 23178882
references.citation: PLoS One. 2007 Sep 26;2(9):e959
references.pmid: 17895999
references.citation: Chem Biol. 2014 Apr 24;21(4):488-501
references.pmid: 24684905
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D91-4
references.pmid: 14681366
references.citation: Development. 2011 Jan;138(1):169-77
references.pmid: 21138979
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17921-6
references.pmid: 24127591
references.citation: Curr Biol. 2005 Feb 8;15(3):249-54
references.pmid: 15694309
references.citation: Pigment Cell Res. 2005 Dec;18(6):411-6
references.pmid: 16280006
references.citation: Nature. 2012 Mar 28;483(7391):603-7
references.pmid: 22460905
references.citation: Cell Stem Cell. 2014 Oct 2;15(4):497-506
references.pmid: 25158936
references.citation: Cell Stem Cell. 2012 Nov 2;11(5):633-48
references.pmid: 22981823
references.citation: Cancer Res. 2013 Sep 15;73(18):5709-18
references.pmid: 23913827
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D854-60
references.pmid: 23074187
references.citation: Genome Res. 2003 Dec;13(12):2700-7
references.pmid: 14613981
references.citation: Cancer Res. 2015 Oct 15;75(20):4272-4282
references.pmid: 26282170
references.citation: Mol Cell Proteomics. 2005 Dec;4(12):1920-32
references.pmid: 16127175
references.citation: Med Oncol. 2013;30(3):648
references.pmid: 23801280
references.citation: Mech Dev. 1999 Jul;85(1-2):133-46
references.pmid: 10415354
references.citation: Dev Dyn. 2007 Nov;236(11):3088-99
references.pmid: 17937395
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13904-9
references.pmid: 23918387
references.citation: Cell. 2013 Nov 7;155(4):934-47
references.pmid: 24119843
references.citation: Immunology. 1958 Jan;1(1):46-54
references.pmid: 13513141
references.citation: Dev Dyn. 2001 Feb;220(2):169-74
references.pmid: 11169850
references.citation: Nat Cell Biol. 2012 Aug;14(8):882-90
references.pmid: 22772081
references.citation: Cell. 2013 Apr 11;153(2):320-34
references.pmid: 23582323
references.citation: Br J Cancer. 2006 Mar 27;94(6):835-41
references.pmid: 16508630
references.citation: Cell. 2013 Apr 11;153(2):307-19
references.pmid: 23582322
references.citation: Nature. 2011 Feb 10;470(7333):279-83
references.pmid: 21160473
references.citation: Nat Methods. 2013 Dec;10(12):1213-8
references.pmid: 24097267
references.citation: Genesis. 2010 Nov;48(11):656-66
references.pmid: 20836130
references.citation: Nat Protoc. 2008;3(1):59-69
references.pmid: 18193022
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Dev Cell. 2015 Mar 23;32(6):756-64
references.pmid: 25752963
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Cancer. 1953 Sep;6(5):963-8
references.pmid: 13094644
references.citation: Nat Methods. 2012 Mar 04;9(4):357-9
references.pmid: 22388286
references.citation: Science. 2014 Nov 21;346(6212):945-9
references.pmid: 25414302
references.citation: Genome Res. 2002 Jun;12(6):996-1006
references.pmid: 12045153
references.citation: Genesis. 2000 Jan;26(1):86-97
references.pmid: 10660676
references.citation: Nat Protoc. 2006;1(2):729-48
references.pmid: 17406303
references.citation: Genome Biol. 2013;14(10):R113
references.pmid: 24148783
references.citation: Nat Biotechnol. 2011 Jan;29(1):24-6
references.pmid: 21221095