MEOX2 enhances DNA repair and therapy resistance in Glioblastoma stem-like cells via PARP1 interaction

Abstract

The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability. Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.