Article Dans Une Revue Cancers Année : 2024

Exosome-Mediated Paracrine Signaling Unveils miR-1246 as a Driver of Aggressiveness in Fusion-Negative Rhabdomyosarcoma

Farah Ramadan
Raya Saab
Farah Ghamloush
  • Fonction : Auteur
Rita Khoueiry
  • Fonction : Auteur
Zdenko Herceg
  • Fonction : Auteur
Bassam Badran
  • Fonction : Auteur
Philippe Clezardin
Nader Hussein
  • Fonction : Auteur
Pascale Cohen
  • Fonction : Auteur
  • PersonId : 997549

Résumé

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.

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hal-04929330 , version 1 (25-02-2025)

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Farah Ramadan, Raya Saab, Farah Ghamloush, Rita Khoueiry, Zdenko Herceg, et al.. Exosome-Mediated Paracrine Signaling Unveils miR-1246 as a Driver of Aggressiveness in Fusion-Negative Rhabdomyosarcoma. Cancers, 2024, 16 (9), pp.1652. ⟨10.3390/cancers16091652⟩. ⟨hal-04929330⟩
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