Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells.
Fiche publication
Date publication
juin 2021
Journal
Scientific reports
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAHRAM Siamak, Dr GOETZ Jacky, Dr LEFEBVRE Olivier, Dr CARAPITO Raphaël, Dr OSMANI Naël
Tous les auteurs :
Follain G, Osmani N, Gensbittel V, Asokan N, Larnicol A, Mercier L, Garcia-Leon MJ, Busnelli I, Pichot A, Paul N, Carapito R, Bahram S, Lefebvre O, Goetz JG
Lien Pubmed
Résumé
Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.
Référence
Sci Rep. 2021 Jun 23;11(1):13144