Journal
CELL
Volume 170, Issue 5, Pages 845-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.07.016
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Funding
- Childhood Brain Tumor Foundation
- Lyla Nsouli Foundation
- Unravel Pediatric Cancer
- National Institute of Neurological Disorders and Stroke [R01NS092597]
- Liwei Wang Research Fund
- Reller Family Research Fund
- Department of Defense [W81XWH-151-0131]
- McKenna Claire Foundation
- Alex's Lemonade Stand Foundation
- Cure Starts Now Foundation
- DIPG Collaborative
- N8 Foundation
- California Institute for Regenerative Medicine [RN3-06510]
- V Foundation
- Joey Fabus Childhood Cancer Foundation
- Wayland Villars DIPG Foundation
- Connor Johnson, Zoey Ganesh, and Declan Gloster Memorial Funds
- Virginia and D.K. Ludwig Fund for Cancer Research
- Child Health Research Institute at Stanford
- Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases
- Cancer Research UK [C13468/A13982, C13468/A23536]
- Cancer Research UK [23536, 13982] Funding Source: researchfish
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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 theSVZin themurine 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: gliomainteractions and potential therapeutic targets to limit glioma invasion.
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