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

Kevin E. Fisher, Anastasia Sacharidou, Amber N. Stratman, Anne M. Mayo, Sarah B. Fisher, Rachel D. Mahan, Michael J. Davis, George E. Davis

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4558-4569
Number of pages12
JournalJournal of cell science
Volume122
Issue number24
DOIs
StatePublished - Dec 15 2009

Keywords

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

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