Cellular Reprogramming of H3K27M Pediatric High-Grade Glioma to Neuron-like State

We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards mature neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures.

In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic or stem-like phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition.