Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation

Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133−/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM. [Display omitted] •Distinct types of GSCs exist in the GBM core versus the invasive edge•Gain of CD109 in tumor cells occurs at the invasive edge in response to IR•IR induced pro-inflammatory response transcriptionally regulates CD109 via C/EBP-β•CD109 drives oncogenic signaling through the YAP/TAZ pathway Minata et al., in response to the proinflammatory environment induced by radiation, find that the tumor cells at the invasive edge acquire the expression of the CD109 protein concomitantly losing CD133. CD109 drives oncogenic signaling through the YAP/TAZ pathway, confers radioresistance to the cells, and represents a new potential therapeutic target for glioblastoma.