CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination
Abstract
CD47 is an innate immune checkpoint that inhibits phagocytosis by myeloid cells, contributing to immune evasion by cancer cells. CD47-blocking antibodies have limited efficacy in glioblastoma (GBM), and the cell-intrinsic role of CD47 is poorly understood. In this study, we show that CD47 is highly expressed at the invasive edge of GBM tumors, and its elevated expression correlates with poor patient survival. We demonstrate that CD47 loss impairs GBM cell proliferation, migration, and invasion, independent of immune activity, and leads to reduced tumor burden and prolonged survival in vivo. Our study identifies ROBO2 signaling as a key downstream effector of CD47 and demonstrates that loss of ROBO2 similarly reduces GBM cell proliferation and migration. Importantly, we have uncovered that CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. These findings establish CD47 as a key regulator of GBM cell plasticity and highlight the therapeutic potential of targeting CD47 – ROBO2 signaling in GBM.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Ruhi Polara
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Briony L. Gliddon
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Raja Ganesan
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Lorena T. Davies
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
John Toubia
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Sakthi Lenin
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Ghizal Siddiqui
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus
Olivia Morris-Hanon
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Melinda N. Tea
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Paul A. B. Moretti
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Dung A. Nguyen
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Chung Hoow Kok
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Chloe Shard
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Alexander H. Staudacher
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Michael P. Brown
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Darren J. Creek
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus
Guillermo A. Gomez
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Daniel Thomas
School of Medicine, College of Health, Adelaide University
Stuart M. Pitson
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Nirmal Robinson
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology