title: Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.
abstract: Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, CA 90095;
authors.forename: Claire M
authors.initials: CM
authors.lastname: Faltermeier
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drake
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Clark
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zong
authors.affiliation: Division of Laboratory and Animal Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Carmen
authors.initials: C
authors.lastname: Volpe
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Colleen
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Department of Urology, University of Washington, Seattle, WA 98195;
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Brandon
authors.initials: B
authors.lastname: Castor
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095; Department of Urology, University of California, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, CA 90095; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095 owenwitte@mednet.ucla.edu.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D016086:Lentivirus; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics; D014781:Viscera / Q000473:pathology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011494:Protein Kinases; D019061:src-Family Kinases
keywords: bone metastasis; kinases; metastasis; prostate cancer