SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Mirjam Blattner; Deli Liu; Brian D Robinson; Dennis Huang; Anton Poliakov; Dong Gao; Srilakshmi Nataraj; Lesa D Deonarine; Michael A Augello; Verena Sailer; Lalit Ponnala; Michael Ittmann; Arul M Chinnaiyan; Andrea Sboner; Yu Chen; Mark A Rubin; Christopher E Barbieri

doi:10.1016/j.ccell.2017.02.004

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Cancer Cell. 2017 Mar 13;31(3):436-451. doi: 10.1016/j.ccell.2017.02.004.

Authors

Mirjam Blattner¹, Deli Liu², Brian D Robinson³, Dennis Huang⁴, Anton Poliakov⁵, Dong Gao⁶, Srilakshmi Nataraj⁴, Lesa D Deonarine⁴, Michael A Augello⁷, Verena Sailer³, Lalit Ponnala⁸, Michael Ittmann⁹, Arul M Chinnaiyan¹⁰, Andrea Sboner¹¹, Yu Chen¹², Mark A Rubin¹³, Christopher E Barbieri¹⁴

Affiliations

¹ 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.
² 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.
³ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
⁴ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
⁵ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
⁷ 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.
⁸ Computational Biology Service Unit, Cornell University, Ithaca, NY 14853, USA.
⁹ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ 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.
¹¹ 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.
¹² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicine, MSKCC, New York, NY 10065, USA.
¹³ 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.
¹⁴ 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.

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.

Keywords: PI3K/mTOR; SPOP; androgen receptor; cancer genomics; organoids; prostate cancer; proteomics; transgenic mouse model.

MeSH terms

Animals
Cell Proliferation
Humans
Male
Mice
Mutation*
Nuclear Proteins / genetics*
Nuclear Receptor Coactivator 3 / physiology
PTEN Phosphohydrolase / genetics
Phosphatidylinositol 3-Kinases / physiology*
Prostatic Neoplasms / etiology*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology
Proto-Oncogene Proteins c-ets / physiology
Receptors, Androgen / physiology*
Repressor Proteins / genetics*
Signal Transduction / physiology*
TOR Serine-Threonine Kinases / physiology*

Substances

Nuclear Proteins
Proto-Oncogene Proteins c-ets
Receptors, Androgen
Repressor Proteins
SPOP protein, human
NCOA3 protein, human
Nuclear Receptor Coactivator 3
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase

Abstract

MeSH terms

Substances

Grants and funding