Article abstract
Nature Cell Biology 9, 893 - 904 (2007)
Published online: 8 July 2007 | doi:10.1038/ncb1616
Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion
Katarina Wolf1, Yi I. Wu2,5, Yueying Liu2, Jörg Geiger3, Eric Tam4,5, Christopher Overall4, M. Sharon Stack2 & Peter Friedl1
Abstract
Invasive cell migration through tissue barriers requires pericellular remodelling of extracellular matrix (ECM) executed by cell-surface proteases, particularly membrane-type-1 matrix metalloproteinase (MT1-MMP/MMP-14). Using time-resolved multimodal microscopy, we show how invasive HT-1080 fibrosarcoma and MDA-MB-231 breast cancer cells coordinate mechanotransduction and fibrillar collagen remodelling by segregating the anterior force-generating leading edge containing 
1 integrin, MT1-MMP and F-actin from a posterior proteolytic zone executing fibre breakdown. During forward movement, sterically impeding fibres are selectively realigned into microtracks of single-cell calibre. Microtracks become expanded by multiple following cells by means of the large-scale degradation of lateral ECM interfaces, ultimately prompting transition towards collective invasion similar to that in vivo. Both ECM track widening and transition to multicellular invasion are dependent on MT1-MMP-mediated collagenolysis, shown by broad-spectrum protease inhibition and RNA interference. Thus, invasive migration and proteolytic ECM remodelling are interdependent processes that control tissue micropatterning and macropatterning and, consequently, individual and collective cell migration.
- Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
- Department of Cell & Molecular Biology, Northwestern University Feinberg Medical School, 303 E. Superior Street, Lurie 3-111, Chicago, Illinois 60611, USA.
- Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Grombuehlstrasse 12, 97080 Würzburg, Germany.
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3 Canada.
- Current addresses: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA (Y.I.W.); Department of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (E.T.)
Correspondence to: Peter Friedl1 e-mail: peter.fr@mail.uni-wuerzburg.de
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