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Katarina Wolf¹, Irina Mazo², Harry Leung³, Katharina Engelke³, Ulrich H. von Andrian⁴, Elena I. Deryugina⁵, Alex Y. Strongin⁵, Eva-B. Bröcker¹ and Peter Friedl¹

¹ Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany
² Department of Pediatrics, Children's Hospital
³ Department of Pathology, Harvard Medical School, Boston, MA 02115
⁴ Center for Blood Research, Harvard Medical School, Boston, MA 02115
⁵ The Burnham Institute, La Jolla, CA 92037

Address correspondence to P. Friedl, Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Tel.: 49-931-20126737. Fax: 49-931-20126700. E-mail: peter.fr{at}mail.uni-wuerzburg.de

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 ß1 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 ß1 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.

Key Words: cell migration; invasion; fibrosarcoma cells; carcinoma cells; matrix proteases

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