Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Claire M. Faltermeier, Justin Drake, Peter M. Clark, Bryan A. Smith, Yang Zong, Carmen Volpe, Colleen Mathis, Colm Morrissey, Brandon Castor, Jiaoti Huang, Owen N. Witte

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)E172-E181
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number2
    DOIs
    StatePublished - Jan 12 2016

    Fingerprint

    Bone Neoplasms
    Prostatic Neoplasms
    Phosphotransferases
    Neoplasm Metastasis
    Prostate
    Castration
    Osteogenesis
    Positron-Emission Tomography
    Protein Kinases
    Mass Spectrometry
    Histology
    Immunohistochemistry
    Tomography
    Gene Expression

    All Science Journal Classification (ASJC) codes

    • General

    Keywords

    • Bone metastasis
    • Kinases
    • Metastasis
    • Prostate cancer

    Cite this

    Faltermeier, Claire M. ; Drake, Justin ; Clark, Peter M. ; Smith, Bryan A. ; Zong, Yang ; Volpe, Carmen ; Mathis, Colleen ; Morrissey, Colm ; Castor, Brandon ; Huang, Jiaoti ; Witte, Owen N. / Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 2. pp. E172-E181.
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    Faltermeier, CM, Drake, J, Clark, PM, Smith, BA, Zong, Y, Volpe, C, Mathis, C, Morrissey, C, Castor, B, Huang, J & Witte, ON 2016, 'Functional screen identifies kinases driving prostate cancer visceral and bone metastasis', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 2, pp. E172-E181. https://doi.org/10.1073/pnas.1521674112

    Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. / Faltermeier, Claire M.; Drake, Justin; Clark, Peter M.; Smith, Bryan A.; Zong, Yang; Volpe, Carmen; Mathis, Colleen; Morrissey, Colm; Castor, Brandon; Huang, Jiaoti; Witte, Owen N.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 2, 12.01.2016, p. E172-E181.

    Research output: Contribution to journalArticle

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    AU - Faltermeier, Claire M.

    AU - Drake, Justin

    AU - Clark, Peter M.

    AU - Smith, Bryan A.

    AU - Zong, Yang

    AU - Volpe, Carmen

    AU - Mathis, Colleen

    AU - Morrissey, Colm

    AU - Castor, Brandon

    AU - Huang, Jiaoti

    AU - Witte, Owen N.

    PY - 2016/1/12

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    N2 - 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.

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