PT  - JOURNAL ARTICLE
AU  - Fisher, Kevin E.
AU  - Sacharidou, Anastasia
AU  - Stratman, Amber N.
AU  - Mayo, Anne M.
AU  - Fisher, Sarah B.
AU  - Mahan, Rachel D.
AU  - Davis, Michael J.
AU  - Davis, George E.
TI  - MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices
AID  - 10.1242/jcs.050724
DP  - 2009 Dec 15
TA  - Journal of Cell Science
PG  - 4558--4569
VI  - 122
IP  - 24
4099  - http://jcs.biologists.org/content/122/24/4558.short
4100  - http://jcs.biologists.org/content/122/24/4558.full
SO  - J. Cell Sci.2009 Dec 15; 122
AB  - 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.