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

被引:280
作者
Kaufman, Charles K. [1 ,2 ,3 ,4 ,5 ]
Mosimann, Christian [6 ]
Fan, Zi Peng [7 ,8 ]
Yang, Song [1 ,2 ,3 ]
Thomas, Andrew J. [1 ,2 ]
Ablain, Julien [1 ,2 ,3 ,5 ]
Tan, Justin L. [1 ,2 ]
Fogley, Rachel D. [1 ,2 ]
van Rooijen, Ellen [1 ,2 ,3 ,5 ]
Hagedorn, Elliott J. [1 ,2 ,3 ,5 ]
Ciarlo, Christie [1 ,2 ,5 ]
White, Richard M. [9 ]
Matos, Dominick A. [10 ]
Puller, Ann-Christin [11 ,12 ]
Santoriello, Cristina [1 ,2 ,13 ]
Liao, Eric C. [3 ,5 ,14 ]
Young, Richard A. [7 ,15 ]
Zon, Leonard I. [1 ,2 ,3 ,4 ,5 ,13 ]
机构
[1] Childrens Hosp Boston, Howard Hughes Med Inst, Stem Cell Program, Boston, MA 02115 USA
[2] Childrens Hosp Boston, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA
[3] Harvard Stem Cell Inst, Boston, MA 02115 USA
[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[5] Harvard Univ, Sch Med, Boston, MA 02115 USA
[6] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland
[7] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA
[8] MIT, Computat & Syst Biol Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA
[9] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY 10075 USA
[10] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA
[11] Childrens Canc Ctr Hamburg, Inst Res, D-20246 Hamburg, Germany
[12] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, D-20246 Hamburg, Germany
[13] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[14] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA
[15] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA
基金
瑞士国家科学基金会; 美国国家卫生研究院;
关键词
SUPER-ENHANCERS; TRANSCRIPTION FACTOR; INHIBITORY-ACTIVITY; CELL IDENTITY; GENE; EXPRESSION; SOX10; CHROMATIN; DISEASE; SYSTEM;
D O I
10.1126/science.aad2197
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:464andaad21971 / aad219710
页数:10
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