Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates

Oncogene. 2009 Apr 2;28(13):1570-83. doi: 10.1038/onc.2009.2. Epub 2009 Feb 23.


The motility of cancer cells in 3D matrices is of two types: mesenchymal motility, in which the cells are elongated and amoeboid motility, in which the cells are round. Amoeboid motility is driven by an actomyosin-based contractile force, which is regulated by the Rho/ROCK pathway. However, the molecular mechanisms underlying the motility of elongated cells remain unknown. Here, we show that the motility of elongated cells is regulated by Rac signaling through the WAVE2/Arp2/3-dependent formation of elongated pseudopodia and cell-substrate adhesion in 3D substrates. The involvement of Rac signaling in cell motility was different in cell lines that displayed an elongated morphology in 3D substrates. In U87MG glioblastoma cells, most of which exhibit mesenchymal motility, inhibition of Rac signaling blocked the invasion of these cells in 3D substrates. In HT1080 fibrosarcoma cells, which display mixed cell motility involving both elongated and rounded cells, inhibition of Rac1 signaling not only blocked mesenchymal motility but also caused a mesenchymal-amoeboid transition. Additionally, Rac1 and RhoA signaling regulated the mesenchymal and amoeboid motility in these cells, respectively, and the inhibition of both pathways dramatically decreased cell invasion. Hence, we could conclude that Rac1 and RhoA signaling simultaneously regulate cell invasion in 3D matrices.

MeSH terms

  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Cell Culture Techniques / methods
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Cell Shape / genetics
  • Cell Shape / physiology
  • Collagen / pharmacology
  • Gels / pharmacology
  • Humans
  • Mutant Proteins / metabolism
  • Mutant Proteins / physiology
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Cells, Cultured
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism
  • rac GTP-Binding Proteins / physiology*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / physiology
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • rho GTP-Binding Proteins / physiology*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / physiology


  • Gels
  • Mutant Proteins
  • RAC1 protein, human
  • RHOA protein, human
  • Collagen
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein