Progenitor Types in the Human Cortex in Normal Development and Glioblastoma

Human cortical development is dependent upon the structured proliferation and differentiation of progenitors into differentiated cell types. This process is tightly regulated by intrinsic and extrinsic cues, which converge to drive human-specific features of the cortex, most notably its expanded size and complexity. On the other hand, glioblastoma (GBM), a highly aggressive primary brain tumor, consists of a heterogeneous mix of neurodevelopmental-like cells that lack control of their proliferation and differentiation. These tumor cells exhibit uncontrollable growth and extreme plasticity, driven by somatic mutations, epigenetic rewiring, microenvironmental interactions, and maladaptive responses to therapy. Recent lineage-tracing and fate-mapping experiments have uncovered unconventional lineage relationships in both normal development and GBM, revealing new cell types along with their origins and progeny. We anticipate that neurodevelopmental perspectives will continue to deepen our understanding of GBM heterogeneity and plasticity, which can then inform the development of cell state reprogramming approaches for therapy.