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

  • Cancer Cell. 2016 Apr 11;29(4):536-547. doi: 10.1016/j.ccell.2016.03.001.
John K Lee  1 ,  John W Phillips  2 ,  Bryan A Smith  2 ,  Jung Wook Park  2 ,  Tanya Stoyanova  2 ,  Erin F McCaffrey  2 ,  Robert Baertsch  3 ,  Artem Sokolov  3 ,  Justin G Meyerowitz  4 ,  Colleen Mathis  2 ,  Donghui Cheng  5 ,  Joshua M Stuart  3 ,  Kevan M Shokat  6 ,  W Clay Gustafson  7 ,  Jiaoti Huang  8 ,  Owen N Witte  9
Affiliations
  • 1. Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2. Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3. Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
  • 4. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 7. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 8. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 9. Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
PMID: 27050099 DOI: 10.1016/j.ccell.2016.03.001
Abstract

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.

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