title: N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer.
abstract: The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dardenne
authors.affiliation: Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA; Tri-Institutional Training Program in Computational Biology and Medicine of Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, and Cornell University, Ithaca, NY 14853, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Gayvert
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Berger
authors.affiliation: Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Loredana
authors.initials: L
authors.lastname: Puca
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cyrta
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA; Tri-Institutional Training Program in Computational Biology and Medicine of Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, and Cornell University, Ithaca, NY 14853, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Zohal
authors.initials: Z
authors.lastname: Noorzad
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: MacDonald
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cheung
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Ka Shing
authors.initials: KS
authors.lastname: Yuen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Juan-Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: dsr2005@med.cornell.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016259:Genes, myc; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D001381:Azepines; C550258:MLN 8237; C459801:MYCN protein, human; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse
keywords: Aurora kinase A; EZH2; N-Myc; castration-resistant prostate adenocarcinoma; genetically engineered mouse; neuroendocrine prostate cancer; prostate cancer organoid