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

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

doi:10.1038/s41467-017-01686-y

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

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

^*Corresponding author for this work

Department of Cancer Research

Research output: Contribution to journal › Article › Research › peer-review

49 Citations (Scopus)

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.

Original language	English
Article number	1571
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01686-y
Publication status	Published - 1 Dec 2017

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title = "The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors",

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.",

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AU - Daubon, Thomas

AU - Lee, Yi Zong

AU - Dedieu, Stephane

AU - Constantin, Marion

AU - Bello, Lorenzo

AU - Rossi, Marco

AU - Bjerkvig, Rolf

AU - Sue, Shih Che

AU - Bikfalvi, Andreas

AU - Billottet, Clotilde

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

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