N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

被引:382
作者
Lee, John K. [1 ,2 ]
Phillips, John W. [3 ]
Smith, Bryan A. [3 ]
Park, Jung Wook [3 ]
Stoyanova, Tanya [3 ]
McCaffrey, Erin F. [3 ]
Baertsch, Robert [4 ]
Sokolov, Artem [4 ]
Meyerowitz, Justin G. [5 ,6 ,7 ,8 ]
Mathis, Colleen [3 ]
Cheng, Donghui [9 ]
Stuart, Joshua M. [4 ]
Shokat, Kevan M. [5 ,8 ]
Gustafson, W. Clay [5 ,10 ]
Huang, Jiaoti [9 ,11 ]
Witte, Owen N. [3 ,9 ,12 ,13 ]
机构
[1] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Dept Microbiol Immunol & Med Genet, Los Angeles, CA 90095 USA
[4] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Jack Baskin Sch Engn, Santa Cruz, CA 95064 USA
[5] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA
[6] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA
[7] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA
[8] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94158 USA
[9] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA
[10] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94158 USA
[11] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA
[12] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA
[13] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA
关键词
STEM-CELL; C-MYC; BASAL-CELLS; CARCINOMA; EXPRESSION; ORIGIN; DIFFERENTIATION; ADENOCARCINOMA; IDENTIFICATION; INACTIVATION;
D O I
10.1016/j.ccell.2016.03.001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.
引用
收藏
页码:536 / 547
页数:12
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