title: Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling.
abstract: The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation.
authors.affiliation: IBISC EA 4526, Evry Val d'Essonne University, Evry, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Cartier-Michaud
authors.forename: Michel
authors.initials: M
authors.lastname: Malo
authors.forename: Cécile
authors.initials: C
authors.lastname: Charrière-Bertrand
authors.forename: Gilles
authors.initials: G
authors.lastname: Gadea
authors.forename: Christelle
authors.initials: C
authors.lastname: Anguille
authors.forename: Ajitha
authors.initials: A
authors.lastname: Supiramaniam
authors.forename: Annick
authors.initials: A
authors.lastname: Lesne
authors.forename: Franck
authors.initials: F
authors.lastname: Delaplace
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hutzler
authors.forename: Pierre
authors.initials: P
authors.lastname: Roux
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Georgia
authors.initials: G
authors.lastname: Barlovatz-Meimon
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects* / Q000378:metabolism*; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D055767:Immobilized Proteins / Q000494:pharmacology; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D055767:Immobilized Proteins; D017395:Plasminogen Activator Inhibitor 1; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D014568:Urokinase-Type Plasminogen Activator; D020742:rhoA GTP-Binding Protein