title: Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis.
abstract: The lungs are ubiquitous receptacles of metastases originating from various bodily tumors. Although osteopontin (SPP1) has been associated with tumor dissemination, the role of its isoforms in lung-directed metastasis is incompletely understood. We employed syngeneic mouse models of spontaneous and induced lung-targeted metastasis inC57BL/6mice competent and deficient in bothSpp1alleles. Tumor-derived osteopontin expression was modulated using either stable anti-Spp1RNA interference, or forced overexpression of intracellular and secretedSpp1isoforms. Identified osteopontin's downstream partners were validated using lung adenocarcinoma cells conditionally lacking theTrp53gene andCcr2-deficient mice. We determined that host-derived osteopontin was dispensable for pulmonary colonization by different tumor types. Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors. As new ways to target osteopontin signaling are becoming available, the cytokine may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Ioanna
authors.identifier: 0000-0003-4393-7517
authors.initials: I
authors.lastname: Giopanou
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Lilis
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Vassilios
authors.identifier: 0000-0001-7324-9796
authors.initials: V
authors.lastname: Papaleonidopoulos
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Agalioti
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Nikolaos I
authors.identifier: 0000-0002-0065-2282
authors.initials: NI
authors.lastname: Kanellakis
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Nikolitsa
authors.initials: N
authors.lastname: Spiropoulou
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras , Rio, Achaia, Greece.
authors.forename: Magda
authors.initials: M
authors.lastname: Spella
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, Greece; Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany.
authors.forename: Georgios T
authors.identifier: 0000-0002-9215-6461
authors.initials: GT
authors.lastname: Stathopoulos
keywords: C–C-motif chemokine ligand 2; inflammation and cancer; secreted phosphoprotein 1; spontaneous lung metastasis; tumor-related protein 53