Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). Glioblastoma stem cells (GSCs) are believed to be responsible for GBM development, progression, invasion, recurrence, and therapeutic resistance. Nevertheless, the detailed molecular mechanisms of these invasive GSCs remain largely unexplored. Here, Prof. Yin’s team found that Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. 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. Mechanically, we demonstrated that IGFBP5 binded to ROR1 can promote the formation of ROR1/HER2 heterodimers, induce phosphorylation of CREB and regulate the expression of ETV5 and FBXW9 at the transcriptional level, thereby promoting GSC invasion and tumorigenesis. At the same time, the team used a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing which significantly suppressed GSC invasion and downstream gene expression, prolonged the survival of GBM in situ tumor-bearing mice. Collectively, the team found that IGFBP5 regulates the invasion of GBM through the ROR1/HER2-CREB signal axis, which provides new therapeutic targets and ideas for GBM treatment.
The research results was published entitled as “IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis” in Nature Communications (IF=17.694). Ph.D. candidate Rui Niu, Prof. Yan Zou from HENU and Weiwei lin, Seong-Min Park, Sung Soo Kim from KNCC shared the first authors. Prof. Bingyang Shi and Prof. Jinlong Yin from HENU and Prof. Jong Bea Park from KNCC shared the co-corresponding authors.
Paper link：https://www.nature.com/articles/s41467-023-37306-1
