IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cancer Genetics

Background:

• Glioblastoma (GBM) recurrence and therapeutic resistance are driven by diffuse infiltration.
• Glioblastoma stem-like cells (GSCs) are responsible for GBM invasion, but targeted therapies remain limited.

Purpose of the Study:

• To identify and validate novel therapeutic targets for inhibiting GSC invasion in glioblastoma.
• To investigate the role of Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) in GSC invasion and tumorigenesis.

Main Methods:

• Glioblastoma stem-like cells (GSCs) were characterized into invasive and non-invasive subtypes using a derived brain tumor model.
• RNA sequencing identified differential expression of IGFBP5 between GSC subtypes.
• In vitro and in vivo experiments assessed the effects of IGFBP5 knockdown and overexpression on GSC invasion.
• CRISPR/Cas9-based IGFBP5 gene editing delivered via nanocapsules was employed in orthotopic tumor models.

Main Results:

• IGFBP5 was identified as a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1) and was differentially expressed in GSCs.
• IGFBP5 modulated GSC invasion capacity, with knockdown inhibiting and overexpression enhancing invasion.
• IGFBP5 promoted GSC invasion by facilitating ROR1/HER2 heterodimer formation and inducing CREB-mediated ETV5 and FBXW9 expression.
• Nanocapsule-mediated CRISPR/Cas9 gene editing of IGFBP5 significantly suppressed GSC invasion, downstream gene expression, and prolonged survival in mice.

Conclusions:

• The IGFBP5-ROR1/HER2-CREB signaling axis represents a critical pathway promoting GSC invasion and tumorigenesis in glioblastoma.
• Targeting IGFBP5, potentially through gene editing strategies, offers a promising therapeutic approach for glioblastoma by inhibiting GSC invasion.