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

John K Lee; John W Phillips; Bryan A Smith; Jung Wook Park; Tanya Stoyanova; Erin F McCaffrey; Robert Baertsch; Artem Sokolov; Justin G Meyerowitz; Colleen Mathis; Donghui Cheng; Joshua M Stuart; Kevan M Shokat; W Clay Gustafson; Jiaoti Huang; Owen N Witte

doi:10.1016/j.ccell.2016.03.001

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. Epub 2016 Mar 31.

Authors

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: owenwitte@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / pathology
Animals
Antineoplastic Agents / therapeutic use
Aurora Kinase A / antagonists & inhibitors
Aurora Kinase A / physiology
Azepines / therapeutic use
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*
Enzyme Activation
Epithelial Cells / metabolism
Epithelial Cells / pathology*
Exome
Gene Expression Regulation, Neoplastic
Genes, myc
Humans
Laser Capture Microdissection
Male
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Neuroendocrine Tumors / genetics*
Neuroendocrine Tumors / pathology
Orchiectomy
Phenylurea Compounds / therapeutic use
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-akt / physiology
Proto-Oncogene Proteins c-myc / physiology*
Pyrimidines / therapeutic use
Recombinant Fusion Proteins / metabolism
Transduction, Genetic
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Azepines
CD532 compound
MLN 8237
Neoplasm Proteins
Phenylurea Compounds
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Pyrimidines
Recombinant Fusion Proteins
AKT1 protein, human
AURKA protein, human
Aurora Kinase A
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding