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

  • Nat Commun. 2017 Nov 17;8(1):1571. doi: 10.1038/s41467-017-01686-y.
Kevin Boyé  1  2 ,  Nadège Pujol  1  2 ,  Isabel D Alves  3 ,  Ya-Ping Chen  4 ,  Thomas Daubon  1  2  5  6 ,  Yi-Zong Lee  4 ,  Stephane Dedieu  7 ,  Marion Constantin  1  2 ,  Lorenzo Bello  8 ,  Marco Rossi  8 ,  Rolf Bjerkvig  5  6 ,  Shih-Che Sue  4 ,  Andreas Bikfalvi  9  10 ,  Clotilde Billottet  11  12
Affiliations
  • 1. INSERM U1029, Pessac, 33615, France.
  • 2. Université de Bordeaux, Pessac, 33615, France.
  • 3. CBMN, UMR 5248 CNRS, Pessac, 33615, France.
  • 4. Institute of Bioinformatics and Structural Biology, NTHU, Hsinchu, 30055, Taiwan.
  • 5. K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, 5009, Norway.
  • 6. Department of Oncology, Luxembourg Institute of Health, Luxembourg, L-1526, Luxembourg.
  • 7. CNRS UMR 7369 MEDyC, Université de Reims Champagne-Ardenne, Reims, 51687, France.
  • 8. Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Humanitas Resarch Hospital, Milan, 20089, Italy.
  • 9. INSERM U1029, Pessac, 33615, France. [email protected].
  • 10. Université de Bordeaux, Pessac, 33615, France. [email protected].
  • 11. INSERM U1029, Pessac, 33615, France. [email protected].
  • 12. Université de Bordeaux, Pessac, 33615, France. [email protected].
PMID: 29146996 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.

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