PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.

Abstract

Background: Glioma stem-like cells (GSCs) are key drivers of treatment resistance and recurrence in glioblastoma (GBM). Phosphoglycerate dehydrogenase (PHGDH), a crucial enzyme in the de novo serine synthesis pathway (SSP), is implicated in tumorigenesis and therapy resistance across various cancers. However, its specific role in GBM, particularly in radioresistance, remains poorly understood.

Methods: In silico analysis of GBM patient data assessed SSP enrichment and PHGDH expression linked with tumor stemness. Comparative gene expression analysis focused on PHGDH in paired GBM specimens and GSCs. Genetic and pharmacological loss-of-function assays were performed in vitro and in vivo to evaluate PHGDH's impact on GSC self-renewal and malignant progression. Comprehensive transcriptomic and metabolomic analyses, along with chromatin immunoprecipitation, mass spectrometry, and various other biochemical assays, were used to elucidate PHGDH-mediated mechanisms in GBM progression and radioresistance.

Results: PHGDH expression is significantly elevated in GSCs, associated with aggressive glioma progression and poor clinical outcomes. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation. Importantly, MYC was identified as a crucial transcriptional regulator of PHGDH expression. Furthermore, genetic ablation or pharmacological inhibition of PHGDH markedly reduced tumor growth and increased tumor sensitivity to radiotherapy, thereby improving survival outcomes in orthotopic GSC-derived and patient-derived GBM xenograft models.

Conclusions: This study underscores the pivotal role of MYC-mediated PHGDH activation in driving GSC malignant progression and radioresistance in GBM. Targeting PHGDH presents a promising approach to enhance radiotherapy efficacy in GBM patients.