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Molècules de senyalització extracel·lular; Mecanismes de la malaltia; Metàstasi Moléculas de señalización extracelular; Mecanismos de la enfermedad; Metástasis Extracellular signalling molecules, Mechanisms of disease; Metastasis Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis. The authors thank Hector Peinado and his laboratory team (Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO)). The authors thank Dr. Manel Bosch for helpful discussion and assistance with confocal microscopy. The authors thank Dr. Anne Spang and Dr Jordi Berenguer for helpful suggestions and discussion on the paper, and Jane Marshall for language review and editing support. This work was supported by Fondo de Investigaciones Sanitarias (PI14/01320), Redes Temáticas de Investigación Cooperativa en Salud (RD12/0036/0057) and CIBERONC (CB16/12/00363). SRC acknowledges support from the Generalitat de Catalunya (2014 SGR 1131). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF.