Blockade of pro-fibrotic response mediated by the miR-143/-145 cluster prevents targeted therapy-induced phenotypic plasticity and resistance in melanoma

Abstract Lineage dedifferentiation towards a mesenchymal-like state is a common mechanism of adaptive response and resistance to targeted therapy in melanoma. Yet, the transcriptional network driving this phenotypic plasticity remains elusive. Remarkably, this cellular state displays myofibroblast and fibrotic features and escapes MAPK inhibitors (MAPKi) through extracellular matrix (ECM) remodeling activities. Here we show that the anti-fibrotic drug Nintedanib/BIBF1120 is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. We also uncovered the molecular networks that regulate the acquisition of this resistant phenotype and its reversion by Nintedanib, pointing the miR-143/-145 pro-fibrotic cluster as a driver of the therapy-resistant 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 of resistant cells. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate phenotypic transition towards 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 as well as contributing to a fine-tuning of 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

The European Commission's position in the field of security and defence : an unconventional actor at a meeting point

Abstract Due to its indirect role in the Common Foreign and Security Policy (CFSP), the European Commission seems to be a marginal actor in European security governance. As a result, there is little analysis of its role in this field. This approach is somewhat misleading because the EU policy-making process is more complex than it appears. The interdependence between the EU's external policies has increased the interaction between supranational institutions and national governments. Moreover, developments in security and defence at the EU level have opened up a window of opportunity for several actors. This paper will show that the structuring of the European field of security and defence is the result of interaction among various actors. From a sociological standpoint, the paper aims to understand the role of the Commission by shedding light, not only on its position in the field, but also on its relations with the other actors, both state and non-state, involved in EU security governance. Using this relational approach, the paper will argue that the Commission is the meeting point for the actors in the field, playing a coordinating role on the one hand, but facing many challenges on the other