Patient-derived glioblastoma stem cells transcriptome regulation by CD109

Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumor. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we study 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 (GP130) 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. Profiling of patient-derived glioblastoma stem cells according to the phenotypic subtypes identified by Neftel et al., 2019 (PMID 31327527) and investigation of the impact of CD109 silencing on the phenotypic states of Mesenchymal and Neuronal Precursor cells.