title: The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style.
abstract: The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the "path generating" mesenchymal to the "path finding" amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of FlorenceIstituto Toscano Tumori.
authors.forename: Francesca
authors.initials: F
authors.lastname: Margheri
authors.forename: Cristina
authors.initials: C
authors.lastname: Luciani
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Anna
authors.initials: A
authors.lastname: Laurenzana
authors.forename: Alessio
authors.initials: A
authors.lastname: Biagioni
authors.forename: Anastasia
authors.initials: A
authors.lastname: Chillà
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fibbi
authors.forename: Mario
authors.initials: M
authors.lastname: Del Rosso
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D022081:Cell Surface Extensions / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D019012:Integrin beta1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator