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- Title
Exosome-Mediated Paracrine Signaling Unveils miR-1246 as a Driver of Aggressiveness in Fusion-Negative Rhabdomyosarcoma.
- Authors
Ramadan, Farah; Saab, Raya; Ghamloush, Farah; Khoueiry, Rita; Herceg, Zdenko; Gomez, Ludovic; Badran, Bassam; Clezardin, Philippe; Hussein, Nader; Cohen, Pascale A.; Ghayad, Sandra E.
- Abstract
Simple Summary: Rhabdomyosarcoma (RMS) is a rare cancer that occurs in children and adolescents. The presence of metastasis is associated with poor outcomes and highlights the need for new non-invasive therapies. Exosomes are small extracellular vesicles that have an important impact on disease biology by altering the behavior of recipient cells. RMS-derived exosomes are enriched in miRNAs which can regulate tumorigenesis and metastasis. This study newly identifies miR-1246 as a key miRNA enriched in the cargo of exosomes derived from RMS cells. MiR-1246 has the potential to be delivered to recipient fibroblasts, effectively altering their phenotype and contributing to their aggressiveness. In a pioneer clinical study, miR-1246 in the serum exosomes of RMS patients was found to be enriched. Our results pave the way for the use of exosomal miR-1246 as a key mediator of cell aggressiveness in RMS, thus representing an attractive future therapeutic target. Rhabdomyosarcoma is a pediatric cancer associated with aggressiveness and a tendency to develop metastases. Fusion-negative rhabdomyosarcoma (FN-RMS) is the most commonly occurring subtype of RMS, where metastatic disease can hinder treatment success and decrease survival rates. RMS-derived exosomes were previously demonstrated to be enriched with miRNAs, including miR-1246, possibly contributing to disease aggressiveness. We aimed to decipher the functional impact of exosomal miR-1246 on recipient cells and its role in promoting aggressiveness. Treatment of normal fibroblasts with FN-RMS-derived exosomes resulted in a significant uptake of miR-1246 paired with an increase in cell proliferation, migration, and invasion. In turn, delivery of miR-1246-mimic lipoplexes promoted fibroblast proliferation, migration, and invasion in a similar manner. Conversely, when silencing miR-1246 in FN-RMS cells, the resulting derived exosomes demonstrated reversed effects on recipient cells' phenotype. Delivery of exosomal miR-1246 targets GSK3β and promotes β-catenin nuclear accumulation, suggesting a deregulation of the Wnt pathway, known to be important in tumor progression. Finally, a pilot clinical study highlighted, for the first time, the presence of high exosomal miR-1246 levels in RMS patients' sera. Altogether, our results demonstrate that exosomal miR-1246 has the potential to alter the tumor microenvironment of FN-RMS cells, suggesting its potential role in promoting oncogenesis.
- Subjects
RISK assessment; CANCER invasiveness; RESEARCH funding; MICRORNA; CELL proliferation; PILOT projects; CELLULAR signal transduction; CELL motility; CYTOSKELETAL proteins; METASTASIS; FIBROBLASTS; CELL lines; RHABDOMYOSARCOMA; EXOSOMES; PHENOTYPES; SIGNAL peptides; DISEASE progression; DISEASE risk factors
- Publication
Cancers, 2024, Vol 16, Issue 9, p1652
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16091652