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Abstract
Chordomas are rare, generally slow-growing spinal tumors that nonetheless exhibit progressive characteristics over time, leading to malignant phenotypes and high recurrence rates despite maximal therapeutic interventions. These tumors are notoriously resistant to therapies and are often located in regions that complicate achieving gross total resections (GTRs). Cell lines from these tumors are rare as well. Given the limited understanding of the molecular mechanisms driving chordoma progression, we sought to investigate whether extracellular vesicles (EVs) might play a role in promoting tumorigenic phenotypes and potential therapeutic targets. We cultured a new chordoma cell line (ARF-8) derived from an extensive clival chordoma that extended back to the cervical spine. We characterized the ARF-8 cellular and EV proteomes, as well as the impacts of ARF-8 EVs on the proteomes and secretomes of recipient cells (both ARF-8 and human osteoblasts) in autocrine and paracrine settings. Our proteomic analyses suggested roles for transforming growth factor beta (TGFB), cell–matrix interactions involving the epithelial-to-mesenchymal transition (EMT), and cell–extracellular matrix (ECM) interactions in cell migration, consistent with a migratory/metastatic tumor phenotype. We demonstrated that ARF-8 tumor cell migration was dependent on general (arginine–glycine–aspartic acid [RGD]-based) integrin activity and that ARF-8 EVs could promote such migration. ARF-8 EVs also prompted proteomic/secretomic changes in human osteoblast cells, again with indications that cell–cell and cell–ECM interactions are activated. All the characteristics typically associated with chordomas as cancers—migration and invasion, therapeutic resistance, metastatic potential—can be driven by tumor EVs. Overall, ARF-8 EVs promoted predicted tumorigenic phenotypes in recipient cells and might serve as potential therapeutic targets for chordomas.