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Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.

Publication ,  Journal Article
Faltermeier, CM; Drake, JM; Clark, PM; Smith, BA; Zong, Y; Volpe, C; Mathis, C; Morrissey, C; Castor, B; Huang, J; Witte, ON
Published in: Proc Natl Acad Sci U S A
January 12, 2016

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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 12, 2016

Volume

113

Issue

2

Start / End Page

E172 / E181

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Viscera
  • Proteomics
  • Protein Kinases
  • Prostatic Neoplasms
  • Phosphoproteins
  • Neoplasm Proteins
  • Mice, SCID
  • Mice
  • Male
 

Citation

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Faltermeier, C. M., Drake, J. M., Clark, P. M., Smith, B. A., Zong, Y., Volpe, C., … Witte, O. N. (2016). Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A, 113(2), E172–E181. https://doi.org/10.1073/pnas.1521674112
Faltermeier, Claire M., Justin M. Drake, Peter M. Clark, Bryan A. Smith, Yang Zong, Carmen Volpe, Colleen Mathis, et al. “Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.Proc Natl Acad Sci U S A 113, no. 2 (January 12, 2016): E172–81. https://doi.org/10.1073/pnas.1521674112.
Faltermeier CM, Drake JM, Clark PM, Smith BA, Zong Y, Volpe C, et al. Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E172–81.
Faltermeier, Claire M., et al. “Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.Proc Natl Acad Sci U S A, vol. 113, no. 2, Jan. 2016, pp. E172–81. Pubmed, doi:10.1073/pnas.1521674112.
Faltermeier CM, Drake JM, Clark PM, Smith BA, Zong Y, Volpe C, Mathis C, Morrissey C, Castor B, Huang J, Witte ON. Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E172–E181.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 12, 2016

Volume

113

Issue

2

Start / End Page

E172 / E181

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Viscera
  • Proteomics
  • Protein Kinases
  • Prostatic Neoplasms
  • Phosphoproteins
  • Neoplasm Proteins
  • Mice, SCID
  • Mice
  • Male