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

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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