Abstract
Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109/STAT3 axis sensitized the GSCs to chemotherapy, suggesting that targeting CD109/STAT3 axis has potential to overcome therapy resistance in glioblastoma.
Highlights
Glioblastoma, the most common malignant primary brain tumor, accounts for 14.5% of all tumors and almost half of the malignant tumors of the CNS [1]
We demonstrate a physical interaction between CD109 and glycoprotein 130 (GP130) that is required for activation of the IL-6/STAT3 signaling pathway in Glioblastoma stem cells (GSCs)
We found no association between CD109 and the IDH1 mutation, p53, or EGFR (Supplemental Table 2)
Summary
Glioblastoma, the most common malignant primary brain tumor, accounts for 14.5% of all tumors and almost half of the malignant tumors of the CNS [1]. The standard of care includes maximal surgical resection followed by treatment with radiation and temozolomide (TMZ) chemotherapy. Despite these efforts, median survival is only approximately 15 months [2]. Glioblastoma stem cells (GSCs) can self-renew, drive tumorigenesis, and promote tumor recurrence following chemotherapy [5,6,7]. GSCs are highly plastic with a capacity for adaptation that fuels tumor heterogeneity and therapy resistance [8,9,10]. Treatment of glioblastoma cells with TMZ induces a phenotypic shift of differentiated tumor cells to a stem-like state [11]. The molecular underpinnings driving GSCs’ plasticity, tumorigenicity, and therapy resistance must be elucidated with potential implications for therapy
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