title: Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.
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.
authors: Department 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.
authors: Justin M
authors: JM
authors: Drake
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Evan O
authors: EO
authors: Paull
authors: Crump 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.
authors: Nicholas A
authors: NA
authors: Graham
authors: 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.
authors: John K
authors: JK
authors: Lee
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Bryan A
authors: BA
authors: Smith
authors: Crump 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.
authors: Bjoern
authors: B
authors: Titz
authors: Department 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.
authors: Tanya
authors: T
authors: Stoyanova
authors: Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Claire M
authors: CM
authors: Faltermeier
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Vladislav
authors: V
authors: Uzunangelov
authors: Department 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.
authors: Daniel E
authors: DE
authors: Carlin
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Daniel Teo
authors: DT
authors: Fleming
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Christopher K
authors: CK
authors: Wong
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Yulia
authors: Y
authors: Newton
authors: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Sud
authors: S
authors: Sudha
authors: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Ajay A
authors: AA
authors: Vashisht
authors: Jonsson 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.
authors: Jiaoti
authors: J
authors: Huang
authors: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: James A
authors: JA
authors: Wohlschlegel
authors: Crump 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.
authors: Thomas G
authors: TG
authors: Graeber
authors: Department 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.
authors: Owen N
authors: ON
authors: Witte
authors: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: jstuart@ucsc.edu.
authors: Joshua M
authors: JM
authors: Stuart
mesh_terms: D000465:Algorithms; D006801:Humans; D008297:Male; D010750:Phosphoproteins / Q000032:analysis*; D057285:Precision Medicine; D064129:Prostatic Neoplasms, Castration-Resistant / Q000737:chemistry* / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D010750:Phosphoproteins; D020543:Proteome