Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma
- 1Belgian Nuclear Research Centre, SCK CEN
Abstract
Glioblastoma (GBM) is characterized by marked heterogeneity, glioma stem-like cells (GSCs), and resistance to therapy. Because GSCs share features with neural progenitor cells (NPCs), we investigated whether neurodevelopmental programs contribute to their response to irradiation. Transcriptional profiling of four patient-derived GSC lines revealed cell line-specific responses, with radiosensitivity correlating with the magnitude of p53 activation and basal expression of its negative regulator, MDM2. Despite this heterogeneity, radiation consistently activated p53-dependent pathways and suppressed cell-cycle programs. Among these, genes associated with primary hereditary microcephaly (MCPH) that regulate NPC proliferation were coordinately repressed. Single-cell RNA sequencing localized this response to G2/M-cycling cells. FOXM1 was similarly reduced following irradiation, emerged as a candidate regulator of a subset of MCPH genes, and correlated with their expression in GBM tumors. Pharmacological inhibition of FOXM1 reduced expression of selected MCPH genes and enhanced radiosensitivity in U251 cells. Together, these findings identify coordinated suppression of a FOXM1-associated MCPH program as part of the GBM radiation response, while suggesting that the radiosensitizing effects of pharmacological FOXM1 inhibition extend beyond this transcriptional axis.
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BibTeX
@misc{eupen2026heterogeneous,
title = {{Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma}},
author = {L. Van Eupen and E. Etlioglu and K. Tabury and K. L. Ligon and I. Aguirre Alcolea and A. Claeys and M. Derweduwe and A. Puspitasari-Kokko and I. Primac and F. De Smet and R. Quintens},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748488},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748488v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma
AU - L. Van Eupen
AU - E. Etlioglu
AU - K. Tabury
AU - K. L. Ligon
AU - I. Aguirre Alcolea
AU - A. Claeys
AU - M. Derweduwe
AU - A. Puspitasari-Kokko
AU - I. Primac
AU - F. De Smet
AU - R. Quintens
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748488
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748488v1
AB - Glioblastoma (GBM) is characterized by marked heterogeneity, glioma stem-like cells (GSCs), and resistance to therapy. Because GSCs share features with neural progenitor cells (NPCs), we investigated whether neurodevelopmental programs contribute to their response to irradiation. Transcriptional profiling of four patient-derived GSC lines revealed cell line-specific responses, with radiosensitivity correlating with the magnitude of p53 activation and basal expression of its negative regulator, MDM2. Despite this heterogeneity, radiation consistently activated p53-dependent pathways and suppressed cell-cycle programs. Among these, genes associated with primary hereditary microcephaly (MCPH) that regulate NPC proliferation were coordinately repressed. Single-cell RNA sequencing localized this response to G2/M-cycling cells. FOXM1 was similarly reduced following irradiation, emerged as a candidate regulator of a subset of MCPH genes, and correlated with their expression in GBM tumors. Pharmacological inhibition of FOXM1 reduced expression of selected MCPH genes and enhanced radiosensitivity in U251 cells. Together, these findings identify coordinated suppression of a FOXM1-associated MCPH program as part of the GBM radiation response, while suggesting that the radiosensitizing effects of pharmacological FOXM1 inhibition extend beyond this transcriptional axis.
ER -