The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors.
Fiche publication
Date publication
novembre 2017
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DEDIEU Stéphane
Tous les auteurs :
Boyé K, Pujol N, D Alves I, Chen YP, Daubon T, Lee YZ, Dedieu S, Constantin M, Bello L, Rossi M, Bjerkvig R, Sue SC, Bikfalvi A, Billottet C
Lien Pubmed
Résumé
CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology.
Mots clés
Animals, Brain Neoplasms, pathology, Cell Membrane, metabolism, Cell Movement, physiology, Chick Embryo, Gene Expression Regulation, Neoplastic, Glioblastoma, pathology, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-1, genetics, Male, Mice, Mice, Knockout, Neoplasm Invasiveness, pathology, Protein Binding, Protein Transport, physiology, Receptors, CXCR3, metabolism, Spheroids, Cellular, Tumor Cells, Cultured
Référence
Nat Commun. 2017 Nov 17;8(1):1571