The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

// Francesca Margheri 1,* , Cristina Luciani 1,* , Maria Letizia Taddei 1 , Elisa Giannoni 1 , Anna Laurenzana 1 , Alessio Biagioni 1 , Anastasia Chillà 1 , Paola Chiarugi 1 , Gabriella Fibbi 1 and Mario Del Rosso 1 1 Department of Experimental and Clinical Biomedical Sciences, University of FlorenceIstituto Toscano Tumori * These authors contributed equally to the study Correspondence: Mario Del Rosso, email: // Gabriella Fibbi, email: // Keywords : uPAR, mesenchymal movement, amoeboid movement, prostate carcinoma, melanoma,Rho-GTPases. Received : December 30, 2013 Accepted : March 8, 2014 Published : March 10, 2014 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.