MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices

• Published in: Journal of cell science Vol. 122; no. 24; pp. 4558 - 4569
• Main Authors: Fisher, Kevin E, Sacharidou, Anastasia, Stratman, Amber N, Mayo, Anne M, Fisher, Sarah B, Mahan, Rachel D, Davis, Michael J, Davis, George E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 15-12-2009; Company of Biologists
• Subjects: cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Line, Tumor; Cell Movement; Collagen - metabolism; Extracellular Matrix - metabolism; Humans; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Models, Biological; Neoplasm Invasiveness; Neoplasms - metabolism; Neoplasms - physiopathology; Signal Transduction
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.050724

Complex signaling events control tumor invasion in three-dimensional (3D) extracellular matrices. Recent evidence suggests that cells utilize both matrix metalloproteinase (MMP)-dependent and MMP-independent means to traverse 3D matrices. Herein, we demonstrate that lysophosphatidic-acid-induced HT1080 cell invasion requires membrane-type-1 (MT1)-MMP-mediated collagenolysis to generate matrix conduits the width of a cellular nucleus. We define these spaces as single-cell invasion tunnels (SCITs). Once established, cells can migrate within SCITs in an MMP-independent manner. Endothelial cells, smooth muscle cells and fibroblasts also generate SCITs during invasive events, suggesting that SCIT formation represents a fundamental mechanism of cellular motility within 3D matrices. Coordinated cellular signaling events are required during SCIT formation. MT1-MMP, Cdc42 and its associated downstream effectors such as MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) and Pak4 (p21 protein-activated kinase 4), protein kinase Cα and the Rho-associated coiled-coil-containing protein kinases (ROCK-1 and ROCK-2) coordinate signaling necessary for SCIT formation. Finally, we show that MT1-MMP and Cdc42 are fundamental components of a co-associated invasion-signaling complex that controls directed single-cell invasion of 3D collagen matrices.