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

作者：Fisher Kevin E; Sacharidou Anastasia; Stratman Amber N; Mayo Anne M; Fisher Sarah B; Mahan Rachel D; Davis Michael J; Davis George E^*

来源：Journal of Cell Science, 2009, 122(24): 4558-4569.

DOI：10.1242/jcs.050724

• MT1-MMP
• Invasion
• Cdc42
• HT1080
• LPA
• Three-dimensional
• Nucleus
• Metastasis
• Extracellular matrix

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 Ca 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 invasionsignaling complex that controls directed single-cell invasion of 3D collagen matrices.

• 出版日期2009-12-15