title: Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis.
abstract: 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 beta 1 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 beta 1 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.
authors.affiliation: Department of Dermatology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Wolf
authors.forename: Irina
authors.initials: I
authors.lastname: Mazo
authors.forename: Harry
authors.initials: H
authors.lastname: Leung
authors.forename: Katharina
authors.initials: K
authors.lastname: Engelke
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Elena I
authors.initials: EI
authors.lastname: Deryugina
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.forename: Eva-B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
mesh_terms: D000199:Actins / Q000378:metabolism; D000656:Amoeba / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D048429:Cell Size / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D016378:Tissue Transplantation; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; C507096:Mmp14 protein, mouse; D011480:Protease Inhibitors; D003094:Collagen; D010450:Endopeptidases; D010447:Peptide Hydrolases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14