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Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities., OMT: Fundación Alba Pérez lucha contra el cáncer infantil. Instituto de Salud Carlos III (CES12/021; PI11/00038; PI15/00035; AC14/00026) and EU's Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa/A way to achieve Europe.” CERCA Program/Generalitat de Catalunya (2017SGR332). OA-R, DH-M: Fundación Científica de la AECC. SG-M, SR-V: Fundación Alba Pérez lucha contra el cáncer infantil. PM: European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement ITN: 766214 – ESR 4.