title: Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion.
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 beta1 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.
authors.affiliation: Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Wolf
authors.forename: Yi I
authors.initials: YI
authors.lastname: Wu
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jörg
authors.initials: J
authors.lastname: Geiger
authors.forename: Eric
authors.initials: E
authors.lastname: Tam
authors.forename: Christopher
authors.initials: C
authors.lastname: Overall
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D048430:Cell Shape; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008853:Microscopy / Q000379:methods; D009361:Neoplasm Invasiveness; D011480:Protease Inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D019012:Integrin beta1; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D003094:Collagen; D053511:Matrix Metalloproteinase 14