Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (scRNA-Seq)

Tumor recurrence afflicts over 95% of glioblastoma (GBM) patients, contributing to the disease's high fatality rates. To unravel the molecular mechanisms behind post-therapy recurrence, we employed a clinically-relevant chemoradiotherapy model, studying the temporal molecular metabolic evolution of patient-derived GBM samples in vitro and in vivo. Leveraging unbiased multi-omics methods, including single-cell and bulk transcriptomics, untargeted metabolomics, and stable isotope tracing, we revealed a dynamic metabolic rewiring favoring one-way anaplerotic pyruvate metabolism via carboxylation across GBM samples. This conserved adaptation, confirmed in independent datasets, resulted in reduced glucose-derived acetyl-coA production, hindering histone acetylation and silencing neural-differentiation genes NEUROD1 and DCX. Pharmacological intervention targeting this metabolic shift reduced recurrent GBM cell aggressiveness, prolonging survival in preclinical GBM xenograft tumors treated with chemoradiotherapy. These findings illuminate a potential metabolic therapeutic avenue to enhance current strategies, addressing disease recurrence and offering much-needed improvements in survival outcomes for GBM patients suffering from this dismal disease.