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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Claire M Faltermeier1, Justin M Drake2, Peter M Clark2

  • 1Molecular Biology Institute, University of California, Los Angeles, CA 90095;

Proceedings of the National Academy of Sciences of the United States of America
|December 2, 2015
PubMed

Insights

Wild-type protein kinases, not mutations, drive prostate cancer metastasis. Specific kinases like RAF, MERTK, and NTRK2 promote bone and visceral metastasis, offering potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Kinases are crucial in cancer progression, but their role in metastatic prostate cancer, particularly non-mutated forms, is under-explored.
  • While oncogenic alterations are common in metastatic prostate cancer, kinase mutations are rare, suggesting alternative mechanisms of kinase involvement.
  • Understanding the specific kinases driving metastasis is critical for developing targeted therapies.

Purpose of the Study:

  • To identify wild-type (non-mutated) kinases that promote metastasis in prostate cancer.
  • To mechanistically link specific kinases to the metastatic cascade in prostate cancer.
  • To evaluate the therapeutic potential of identified kinases in metastatic prostate cancer.

Main Methods:

  • Utilized mass spectrometry-based phosphoproteomics and gene expression analysis to identify candidate kinases.
  • Conducted in vivo screens using murine and human prostate cells to assess the metastatic potential of overexpressed kinases.
  • Employed positron-emission tomography-computed tomography imaging and histology for metastasis confirmation.
  • Analyzed immunohistochemistry of tissue microarrays to determine kinase expression in human metastatic prostate cancer.

Main Results:

  • Identified over 100 kinases potentially implicated in metastatic prostate cancer.
  • A primary screen identified 20 wild-type kinases that promote metastasis in murine prostate cells.
  • RAF family members, MERTK, and NTRK2 were found to drive bone and visceral metastasis in human prostate cells.
  • These kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues.

Conclusions:

  • Select wild-type protein kinases possess a strong capability to drive critical steps of the metastatic cascade in prostate cancer.
  • RAF family members, MERTK, and NTRK2 are key drivers of prostate cancer metastasis to bone and visceral organs.
  • These identified kinases represent potential therapeutic targets for intervention in metastatic prostate cancer.
Keywords:
bone metastasiskinasesmetastasisprostate cancer

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