Twist1-induced invadopodia formation promotes tumor metastasis

Cancer Cell. 2011 Mar 8;19(3):372-86. doi: 10.1016/j.ccr.2011.01.036.

Abstract

The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation in response to various EMT-inducing signals. Induction of PDGFRα and invadopodia is essential for Twist1 to promote tumor metastasis. Consistent with PDGFRα being a direct transcriptional target of Twist1, coexpression of Twist1 and PDGFRα predicts poor survival in breast tumor patients. Therefore, invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Base Sequence
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Surface Extensions / metabolism
  • Cell Surface Extensions / physiology*
  • Electrophoresis, Polyacrylamide Gel
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / physiopathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • RNA Interference
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Twist-Related Protein 1 / physiology*
  • src Homology Domains / genetics

Substances

  • Adaptor Proteins, Vesicular Transport
  • Nuclear Proteins
  • SH3PXD2A protein, human
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • Receptor, Platelet-Derived Growth Factor alpha