Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma

Arthur Bassot (1) , Helena Dragic (1) , Sarah Al Haddad (2) , Laurine Moindrot (2) , Soline Odouard (2) , Francesca Corlazzoli (3) , Eliana Marinari (3) , Alexandra Bomane (1) , Augustin Brassens (1) , Antoine Marteyn (2) , Youssef Hibaoui (1) , Tom J Petty (4) , Mounira Chalabi-Dchar (1) , Louis Larrouquere (1) , Evgeny M Zdobnov (4) , Noémie Legrand (2, 5) , Jérôme Tamburini (2, 3) , Hubert Lincet (1) , Marie Castets (1) , Mayra Yebra (6) , Denis Migliorini (2) , Valérie Dutoit (3, 2) , Paul R Walker (2, 3) , Olivier Preynat-Seauve (2) , Pierre-Yves Dietrich (3, 2) , Erika Cosset (1, 2)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 Geneva University Hospitals and Geneva University
3 SCCL - Swiss Cancer Center Léman [Lausanne, Suisse]
4 SIB - Swiss Institute of Bioinformatics [Genève]
5 INFINITE (Ex-Liric) - Institute for Translational Research in Inflammation - U 1286
6 Moores Cancer Center [La Jolla]

Glioblastoma (GBM) is a deadly and the most common primary brain tumor in adults. Due to their regulation of a high number of mRNA transcripts, microRNAs (miRNAs) are key molecules in the control of biological processes and are thereby promising therapeutic targets for GBM patients. In this regard, we recently reported miRNAs as strong modulators of GBM aggressiveness. Here, using an integrative and comprehensive analysis of the TCGA database and the transcriptome of GBM biopsies, we identified three critical and clinically relevant miRNAs for GBM, miR-17-3p, miR-222, and miR-340. In addition, we showed that the combinatorial modulation of three of these miRNAs efficiently inhibited several biological processes in patient-derived GBM cells of all these three GBM subtypes (Mesenchymal, Proneural, Classical), induced cell death, and delayed tumor growth in a mouse tumor model. Finally, in a doxycycline-inducible model, we observed a significant inhibition of GBM stem cell viability and a significant delay of orthotopic tumor growth. Collectively, our results reveal, for the first time, the potential of miR-17-3p, miR-222 and miR-340 multi-targeting as a promising therapeutic strategy for GBM patients.

Domains: Cancer

Arthur Bassot, Helena Dragic, Sarah Al Haddad, Laurine Moindrot, Soline Odouard, et al.. Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma. Cell Death and Disease, 2023, 14, ⟨10.1038/s41419-023-06117-z⟩. ⟨hal-04231610⟩