Compensation Mechanism in Tumor Cell Migration: Mesenchymal-Amoeboid Transition after Blocking of Pericellular Proteolysis

• Published in: The Journal of cell biology Vol. 160; no. 2; pp. 267 - 277
• Main Authors: Wolf, Katarina, Mazo, Irina, Leung, Harry, Engelke, Katharina, von Andrian, Ulrich H., Deryugina, Elena I., Strongin, Alex Y., Eva-B. Bröcker, Friedl, Peter
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 20-01-2003; The Rockefeller University Press
• Subjects: Actins - metabolism; Amoeba - cytology; Amoeba - metabolism; Animals; Cell lines; Cell motility; Cell Movement - physiology; Cell Size - physiology; Cells; Cellular biology; Cocktails; Collagen - metabolism; Collagens; Dermis - cytology; Dermis - metabolism; Endopeptidases - drug effects; Endopeptidases - metabolism; Extracellular Matrix Proteins - metabolism; Female; Humans; Integrin beta1 - metabolism; Integrins; Matrix Metalloproteinase 14; Matrix Metalloproteinases, Membrane-Associated; Mesoderm - cytology; Mesoderm - metabolism; Mesoderm - transplantation; Metalloendopeptidases - metabolism; Mice; Microscopy; Neoplasm Metastasis - physiopathology; Neoplasms - metabolism; Peptide Hydrolases - metabolism; Protease inhibitors; Protease Inhibitors - pharmacology; T lymphocytes; Tissue Transplantation; Tumor Cells, Cultured; Tumors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200209006

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor-based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1-matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.