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Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

M A Smit1, D S Peeper

  • 1Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.

Oncogene
|April 12, 2011
PubMed

Insights

Anoikis resistance, a key factor in cancer metastasis, is suppressed by TrkB signaling. This study reveals Zeb1 is essential for TrkB-driven epithelial-mesenchymal transition, invasion, and metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Anoikis (detachment-induced apoptosis) normally prevents cancer cell survival and metastasis.
  • The neurotrophic tyrosine kinase receptor TrkB was identified as a suppressor of anoikis.
  • Activated TrkB promotes epithelial cell transformation, invasion, and metastasis, resembling epithelial-mesenchymal transition (EMT).

Purpose of the Study:

  • To investigate the role of Zeb1 in TrkB-mediated anoikis resistance and metastasis.
  • To determine if Zeb1 acts downstream of known TrkB-regulated EMT factors (Twist, Snail).

Main Methods:

  • Functional genome-wide screen to identify TrkB as an anoikis suppressor.
  • RNA interference (RNAi)-mediated knockdown of Zeb1 in epithelial cells.
  • Assessment of morphological changes, anoikis resistance, migration, invasion, and in vivo metastasis.
  • Epistasis experiments to define the genetic hierarchy.

Main Results:

  • Zeb1 knockdown reversed TrkB-induced morphological changes and epithelial-mesenchymal transition (EMT).
  • Zeb1 is required for TrkB-induced anoikis resistance, cell migration, and invasion.
  • In vivo, Zeb1 knockdown significantly reduced TrkB-driven metastasis, acting downstream of Twist and Snail.

Conclusions:

  • Zeb1 is a critical mediator of TrkB-induced epithelial-mesenchymal transition (EMT) and anoikis resistance.
  • Zeb1 plays an essential role in TrkB-driven cancer cell invasion and metastasis.
  • Targeting Zeb1 may offer a therapeutic strategy against TrkB-driven cancers.

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