The Elusive Origin of Glioblastoma: Where Do We Stand?

Glioblastoma (GBM) remains one of the most lethal cancers, and despite advancements in understanding its underlying molecular signature, effective therapeutics are still lacking. The multifaceted challenges of designing treatments for GBM are compounded by the inability to identify a definitive cell of origin, the understanding of which is crucial for developing impactful therapies and ultimately improving patient outcomes. High-resolution technologies, including single-cell and single-nucleus RNA sequencing, spatial transcriptomics, multi-omics, next generation glioma models, bioinformatics, and artificial intelligence are creating an important opportunity to comprehensively map the cellular origin of GBM and its evolutionary dynamics. Accumulating evidence support neural stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) as primary candidates, providing critical insights into the ontogeny of GBM. This comprehensive review synthesizes current knowledge on the cellular origins of GBM and evaluates advanced methodologies, deepening our understanding of its development.