title: SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling.
abstract: Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Blattner
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Deli
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huang
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Poliakov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Nataraj
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Lesa D
authors.initials: LD
authors.lastname: Deonarine
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Augello
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Sailer
authors.affiliation: Computational Biology Service Unit, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Lalit
authors.initials: L
authors.lastname: Ponnala
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Departments of Pathology and Urology, and Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine, and New York-Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicine, MSKCC, New York, NY 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine, and New York-Presbyterian Hospital, New York, NY 10065, USA. Electronic address: rubinma@med.cornell.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: chb9074@med.cornell.edu.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D056921:Nuclear Receptor Coactivator 3 / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000502:physiology; D011944:Receptors, Androgen / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D056921:Nuclear Receptor Coactivator 3; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D050783:Proto-Oncogene Proteins c-ets; D011944:Receptors, Androgen; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; C509761:SPOP protein, human; C538866:NCOA3 protein, human
keywords: PI3K/mTOR; SPOP; androgen receptor; cancer genomics; organoids; prostate cancer; proteomics; transgenic mouse model