Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability

Oncogene. 2015 Aug 20;34(34):4531-44. doi: 10.1038/onc.2014.388. Epub 2014 Dec 8.


Invadopodia are actin-rich cell membrane projections used by invasive cells to penetrate the basement membrane. Control of invadopodia stability is critical for efficient degradation of the extracellular matrix (ECM); however, the underlying molecular mechanisms remain poorly understood. Here, we uncover a new role for podoplanin, a transmembrane glycoprotein closely associated with malignant progression of squamous cell carcinomas (SCCs), in the regulation of invadopodia-mediated matrix degradation. Podoplanin downregulation in SCC cells impairs invadopodia stability, thereby reducing the efficiency of ECM degradation. We report podoplanin as a novel component of invadopodia-associated adhesion rings, where it clusters prior to matrix degradation. Early podoplanin recruitment to invadopodia is dependent on lipid rafts, whereas ezrin/moesin proteins mediate podoplanin ring assembly. Finally, we demonstrate that podoplanin regulates invadopodia maturation by acting upstream of the ROCK-LIMK-Cofilin pathway through the control of RhoC GTPase activity. Thus, podoplanin has a key role in the regulation of invadopodia function in SCC cells, controlling the initial steps of cancer cell invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Surface Extensions / physiology*
  • Extracellular Matrix / metabolism*
  • Humans
  • Lim Kinases / physiology
  • Membrane Glycoproteins / physiology*
  • Membrane Microdomains / physiology
  • Signal Transduction
  • rho GTP-Binding Proteins / physiology
  • rho-Associated Kinases / physiology
  • rhoC GTP-Binding Protein


  • Membrane Glycoproteins
  • PDPN protein, human
  • LIMK1 protein, human
  • Lim Kinases
  • rho-Associated Kinases
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoC GTP-Binding Protein