The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors

Kevin Boyé,Shih-Che Sue,Yi-Zong Lee,Isabel D Alves,Andreas Bikfalvi,Thomas Daubon,Rolf Bjerkvig,Lorenzo Bello,Marion Constantin,Ya-Ping Chen,Stephane Dedieu,Marco Rossi,Clotilde Billottet,Nadège Pujol

doi:10.1038/s41467-017-01686-y

Abstract

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.

Highlights

CXCR3 plays important roles in angiogenesis, inflammation, and cancer
This study reports an interaction between a classical CXC chemokine receptor and Lipoprotein receptor-related protein-1 (LRP1), and shows a regulatory role of LRP1 in G-protein-coupled receptors (GPCRs) conformation, trafficking, and biological activity in tumor cells
We investigated the expression of CXCR3 isoforms in different glioma cell lines (Supplementary Fig. 1A) by quantitative real-time PCR to distinguish CXCR3-A from CXCR3-B

Summary

Introduction

CXCR3 plays important roles in angiogenesis, inflammation, and cancer. 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. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3A 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. CXCR3-A is reported to promote cell proliferation, survival and migration, while CXCR3-B mediates growth inhibitory activity and apoptosis[6,7,8,9]. Many reports have shown that in various cell types (pericytes, endothelial cells, myofibroblast, T cells, epithelial cells, and tumor cells), binding of CXC chemokines to CXCR3 induces activation of p38 and ERK/mitogen activated protein kinases (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C (PLC) 11–14

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Conclusion