Oncotarget

Research Papers:

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

Francesca Margheri, Cristina Luciani, Maria Letizia Taddei, Elisa Giannoni, Anna Laurenzana, Alessio Biagioni, Anastasia Chillà, Paola Chiarugi, Gabriella Fibbi and Mario Del Rosso _

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Oncotarget. 2014; 5:1538-1553. https://doi.org/10.18632/oncotarget.1754

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Abstract

Francesca Margheri1,*, Cristina Luciani1,*, Maria Letizia Taddei1, Elisa Giannoni1, Anna Laurenzana1, Alessio Biagioni1, Anastasia Chillà1, Paola Chiarugi1, Gabriella Fibbi1 and Mario Del Rosso1

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.


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