NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14
Jennifer Patritti-Cram,
Eric P. Rahrmann,
Tilat A. Rizvi,
Katherine C. Scheffer,
Timothy N. Phoenix,
David A. Largaespada,
Nancy Ratner
Affiliations
Jennifer Patritti-Cram
Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0713, USA
Eric P. Rahrmann
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
Tilat A. Rizvi
Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Katherine C. Scheffer
Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Timothy N. Phoenix
Division of Pharmaceutical Sciences, James L. Wrinkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA
David A. Largaespada
Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Nancy Ratner
Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Corresponding author
Summary: The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human NF1 deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition. Conditional Nf1 loss in murine SCs recapitulated these alterations and revealed decreased tight junctions and decreased caveolin-1 (Cav1) expression in mutant nerves and in tumors, implicating reduced Cav1-mediated transcytosis in barrier disruption and tumorigenesis. Additionally, elevated receptor tyrosine kinase activity and genetic deletion of Cav1 increased endoneurial fibrin(ogen), and promoted SC tumor formation. Finally, when SC lacked Nf1, genetic loss or pharmacological inhibition of P2RY14 rescued Cav1 expression and barrier function. Thus, loss of Nf1 in SC causes dysfunction of the BNB via P2RY14-mediated G-protein coupled receptor (GPCR) signaling.
