Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2016 Aug 11;166(4):1041-54. doi: 10.1016/j.cell.2016.07.007. Epub 2016 Aug 4.

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

Author information

  • 1Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Rutgers Cancer Institute of New Jersey and Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA. Electronic address: justin.drake@cinj.rutgers.edu.
  • 2Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
  • 3Crump Institute for Molecular Imaging, 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; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
  • 4Division 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.
  • 5Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6Crump Institute for Molecular Imaging, 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.
  • 7Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA 94304, USA.
  • 8Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 9Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 10Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 11Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 12Jonsson Comprehensive Cancer Center, 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; 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, Duke University School of Medicine, Durham, NC 27710, USA.
  • 13Crump Institute for Molecular Imaging, 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; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 14Department of Microbiology, Immunology, and Molecular Genetics, 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, David Geffen School of Medicine, 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. Electronic address: owenwitte@mednet.ucla.edu.
  • 15Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: jstuart@ucsc.edu.

Abstract

We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

PMID:
27499020
PMCID:
PMC4985183
[Available on 2017-08-11]
DOI:
10.1016/j.cell.2016.07.007
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for eScholarship, California Digital Library, University of California
    Loading ...
    Support Center