Promotion of glioblastoma invasion and progression by IGFBP5

Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem cell (GSC) which is responsible for GBM invasion are yet well established. Herein, we report insulin-like growth factor-binding protein 5 (IGFBP5) as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. Subsequent mechanisms of IGFBP5-triggered oncogenic signaling was demonstrated, which in detail, is mediated by activating HER2 and ROR1, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-HER2/ROR1-CREB signaling axis as a potential GBM therapeutic target