Les travaux de recherche de l’équipe MICROCAN ont été récompensés par la sélection « Article du mois » de la Société française de biochimie et de biologie moléculaire (SFBBM) pour le mois de Mai 2022. L’article sélectionné est issu des travaux de thèse du Dr Serena DIAZZI, sous la co-supervision des Dr Sophie TARTARE-DECKERT et Bernard MARI.

Diazzi, S., A. Baeri, J. Fassy, M. Lecacheur, O. Marin-Bejar, C. A. Girard, L. Lefevre, C. Lacoux, M. Irondelle, C. Mounier, M. Truchi, M. Couralet, M. Ohanna, A. Carminati, I. Berestjuk, F. Larbret, D. Gilot, G. Vassaux, J. C. Marine, M. Deckert, B. Mari and S. Tartare-Deckert (2022). « Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma. » EMBO Mol Med 14(3): e15295.

Résumé de l’article:

Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p, collaborated to mediate transition toward a drug-resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof of principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

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