Abstract
The current standard-of-care treatment for GBM is ineffective and fails to significantly prolong survival. Following exposure to aggressive multimodal treatment, GBMs have been shown to frequently shift their biological features upon recurrence, acquiring a more resistant phenotype. However, the temporal dynamics and molecular mechanisms that facilitate GBM recurrence are poorly understood. The objective of our study was to assess the acute response to ionizing radiation in glioma stem cells (GSCs) from the Classical subtype of GBM in vitro and in vivo. We find that Classical GSCs rapidly undergo dramatic molecular and cellular changes in response to single and fractionated doses of ionizing radiation, resulting in a heterogeneous cell population. Ionizing radiation causes a transient decrease in the expression of key stemness genes (e.g., SOX2) followed by drastic morphological changes and a concomitant significant increase in the levels of key cell fate markers expressed in adult quiescent neural stem cells. Radiation-induced alteration of SOX2 levels in Classical GSCs is dependent on intact p53 signaling. GSCs previously exposed to radiation are more radio-resistant upon re-treatment compared to their naïve, untreated counterparts – suggesting that the aforementioned phenotypic shift to a quiescent neural stem cell phenotype promotes treatment resistance. Our results suggest that cell-intrinsic factors dictate how GSCs respond to radiation, and that Classical GSCs are neurodevelopmentally predisposed to shift towards an astrocytic/neural stem cell identity in response to cellular stress.
Erratum to: The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells
