Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

Elizabeth Y Qin; Dominique D Cooper; Keene L Abbott; James Lennon; Surya Nagaraja; Alan Mackay; Chris Jones; Hannes Vogel; Peter K Jackson; Michelle Monje

doi:10.1016/j.cell.2017.07.016

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

Cell. 2017 Aug 24;170(5):845-859.e19. doi: 10.1016/j.cell.2017.07.016. Epub 2017 Aug 17.

Authors

Affiliations

¹ Department of Neurology, Stanford University, Palo Alto, CA 94305, USA.
² Baxter Laboratory, Department of Microbiology & Immunology, Stanford University, Palo Alto, CA 94305, USA.
³ Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
⁴ Department of Neurology, Stanford University, Palo Alto, CA 94305, USA; Department of Pathology, Stanford University, Palo Alto, CA 94305, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA 94305, USA; Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA.
⁵ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University, Palo Alto, CA 94305, USA; Department of Pathology, Stanford University, Palo Alto, CA 94305, USA.
⁶ Department of Neurology, Stanford University, Palo Alto, CA 94305, USA; Department of Pathology, Stanford University, Palo Alto, CA 94305, USA; Department of Neurosurgery, Stanford University, Palo Alto, CA 94305, USA; Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA. Electronic address: mmonje@stanford.edu.

Abstract

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.

Keywords: HSP90; SPARC; SPARCL1; diffuse intrinsic pontine glioma; glioblastoma; invasion; neural precursor cell; pleiotrophin; subventricular zone.

MeSH terms

Aged
Animals
Brain Neoplasms / metabolism
Brain Neoplasms / pathology*
Carrier Proteins / metabolism*
Cell Communication
Child
Cytokines / metabolism*
Drug Delivery Systems
Female
Glioma / drug therapy
Glioma / pathology*
HSP90 Heat-Shock Proteins / antagonists & inhibitors
Heterografts
Humans
Lateral Ventricles / metabolism
Lateral Ventricles / pathology*
Male
Mice
Neoplasm Invasiveness / pathology*
Neoplasm Transplantation
Signal Transduction
rho GTP-Binding Proteins / metabolism

Substances

Carrier Proteins
Cytokines
HSP90 Heat-Shock Proteins
pleiotrophin
rho GTP-Binding Proteins

Abstract

MeSH terms

Substances

Grants and funding