Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance

Simple Summary Glioblastoma stem cells (GSCs) are characterized by high radioresistance and are responsible for the frequent recurrence of glioblastoma (GBM); therefore, it is imperative to better understand the molecular mechanisms and identify the novel factors involved in these processes. Here, we report that GDF15, a cytokine belonging to the TGF-beta superfamily, is induced by irradiation (IR) and the transcription factor, WWTR1/TAZ. It also promotes GSC radioresistance. These data suggest that blocking GDF15 may be a novel approach in radiosensitizing GSCs.Abstract GSCs play an important role in GBM recurrence. Understanding the resistance mechanisms in these cells is therefore crucial for radiation therapy optimization. In this study, using patient-derived GSCs, we demonstrate that GDF15, a cytokine belonging to the TGF-beta superfamily, is regulated by irradiation (IR) and the transcription factor WWTR1/TAZ. Blocking WWTR1/TAZ using specific siRNAs significantly reduces GDF15 basal expression and reverses the upregulation of this cytokine induced by IR. Furthermore, we demonstrate that GDF15 plays an important role in GSC radioresistance. Targeting GDF15 expression by siRNA in GSCs expressing high levels of GDF15 sensitizes the cells to IR. In addition, we also found that GDF15 expression is critical for GSC spheroid formation, as GDF15 knockdown significantly reduces the number of GSC neurospheres. This study suggests that GDF15 targeting in combination with radiotherapy may be a feasible approach in patients with GBM.