Abstract
Glioblastoma is the most malignant primary brain tumor, the prognosis of which remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared with NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor β (PDGFRβ) proliferative and stem cell signaling pathways through posttranscriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft–bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.
Authors
Ryan C. Gimple, Guoxin Zhang, Shuai Wang, Tengfei Huang, Jina Lee, Suchet Taori, Deguan Lv, Deobrat Dixit, Matthew E. Halbert, Andrew R. Morton, Reilly L. Kidwell, Zhen Dong, Briana C. Prager, Leo J.Y. Kim, Zhixin Qiu, Linjie Zhao, Qi Xie, Qiulian Wu, Sameer Agnihotri, Jeremy N. Rich
Figure 11
SNX10 maintains PDGFRβ protein stability via a posttranscriptional mechanism and alters sensitivity to multitargeted kinase inhibitors.
