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

• DOI: 10.1038/onc.2009.2
• Publication Date: 2009-02-23T11:04:36Z
• Authors: D Yamazaki; S Kurisu; T Takenawa
• Keywords: rac1 GTP-Binding Protein; rho GTP-Binding Proteins; 0301 basic medicine; Cell Culture Techniques; rac GTP-Binding Proteins; 3. Good health; 03 medical and health sciences; Cell Movement; Neoplasms; Cell Adhesion; Tumor Cells, Cultured; Humans; Mutant Proteins; Neoplasm Invasiveness; Collagen; rhoA GTP-Binding Protein; Cell Shape; Gels; Signal Transduction

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.