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2026

Proc Natl Acad Sci U S A . 2026 Mar 31;123(13):e2602460123. doi: 10.1073/pnas.2602460123. Epub 2026 Mar 23.

CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination

Ruhi Polara, Briony L Gliddon, Raja Ganesan, Lorena T Davies, John Toubia, Sakthi Lenin, Ghizal Siddiqui, Olivia Morris-Hanon, Melinda N Tea, Paul A B Moretti, Dung A Nguyen, Chung Hoow Kok, Chloe Shard, Alexander H Staudacher, Michael P Brown, Darren J Creek, Guillermo A Gomez, Daniel Thomas, Stuart M Pitson, Nirmal Robinson

Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology, Adelaide, SA 5001, Australia. Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, University Clinic Cologne, Cologne 50931, Germany. Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA 5000, Australia. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC 3052, Australia. School of Medicine, College of Health, Adelaide University, Adelaide, SA 5000, Australia. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia. Department of Hematology and Bone Marrow Transplantation, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. School of Biological Sciences, College of Science, Adelaide University, Adelaide, SA 5005, Australia.

Service type: Stock strains

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.