Glioblastoma progression is hindered by melatonin-primed mesenchymal stromal cells through dynamic intracellular and extracellular reorganizations

Background. Glioblastoma (GBM) is the deadliest form of brain cancer and its treatment remains an unresolved challenge. Mesenchymal stromal cells (MSCs) have been explored as vehicles for the targeted delivery of anticancer drugs due to their tumor-homing abilities. However, their clinical application is limited due to the controversial role of MSCs on carcinogenesis. This study investigates how MSCs influence tumor behavior and explores the synergistic anticancer effects of the cytoprotective melatonin (Mel). Methods. Orthotopic and subcutaneous GBM xenograft mouse models were used to assess the antitumor effect of Mel pre-treated MSCs (MSCMel). Histological, immunohistochemistry and ultrastructural analysis were conducted to identify phenotypic changes in the tumors. A set of in vitro assays, including direct and indirect co-cultures, dynamic single-cell tracking and tumorsphere migration assay, was conducted to explore the impact of MSCMel on primary and non-primary GBM cells. Transcriptome profiling was used to identify genes and pathways modulated by the synergistic therapy. Results. MSCMel delayed tumor growth in mice and increased collagen deposition. Additionally, MSCMel showed enhanced capacity to prevent GBM cell migration than untreated MSCs. Molecular analysis identified genes and pathways related to cell migration, cytoskeletal dynamics and extracellular matrix remodeling in GBM cells exposed to MSCMel, including extensive reduction of vimentin expression. Finally, a gene signature associated with the clinical outcomes of GBM patients was identified. Conclusions. Our study demonstrates that melatonin enhances the anticancer properties of MSCs, providing new insights on their interaction with GBM cells and the tumor environment. These findings offer valuable guidance for advancing MSC-based therapies in clinical practice.