Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis.
Rho family GTPases regulate the cytoskeleton and cell migration and are frequently overexpressed in tumours. Here, we identify two modes of tumour-cell motility in 3D matrices that involve different usage of Rho signalling. Rho signalling through ROCK promotes a rounded bleb-associated mode of motility that does not require pericellular proteolysis. This form of motility requires ezrin, which is localized in the direction of cell movement. In contrast, elongated cell motility is associated with Rac-dependent F-actin-rich protrusions and does not require Rho, ROCK or ezrin function. Combined blockade of extracellular proteases and ROCK negates the ability of tumour cells to switch between modes of motility and synergises to prevent tumour cell invasion.
Sahai
Erik
E
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
Marshall
Christopher J
CJ
D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement / Q000502:physiology*; D048429:Cell Size; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases; D000099149:Ezrin
D003094:Collagen; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D010447:Peptide Hydrolases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D000099149:Ezrin; C059485:matrigel