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

Weiwei Lin, Rui Niu, Seong-Min Park, Yan Zou, Sung Soo Kim, Xue Xia, Songge Xing, Qingshan Yang, Xinhong Sun, Zheng Yuan, Shuchang Zhou, Dongya Zhang, Hyung Joon Kwon, Saewhan Park, Chan Kim, Harim Koo, Yang Liu, Haigang Wu, Meng Zheng, Heon Yoo, Bingyang Shi (), Jong Bae Park () and Jinlong Yin ()
Additional contact information
Weiwei Lin: Henan University
Rui Niu: Henan University
Seong-Min Park: National Cancer Center
Yan Zou: Henan University
Sung Soo Kim: National Cancer Center
Xue Xia: Henan University
Songge Xing: Henan University
Qingshan Yang: Henan University
Xinhong Sun: Henan University
Zheng Yuan: Henan University
Shuchang Zhou: Henan University
Dongya Zhang: Henan University
Hyung Joon Kwon: National Cancer Center
Saewhan Park: National Cancer Center
Chan Kim: National Cancer Center
Harim Koo: National Cancer Center
Yang Liu: Henan University
Haigang Wu: Henan University
Meng Zheng: Henan University
Heon Yoo: National Cancer Center
Bingyang Shi: Henan University
Jong Bae Park: Henan University
Jinlong Yin: Henan University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report 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. 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. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, 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-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.

Date: 2023
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DOI: 10.1038/s41467-023-37306-1

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