Cell-of-origin-specific behavioral deficits in oligodendrocyte-derived glioblastoma.

Glioblastoma (GBM) remains the most lethal primary brain tumor, persisting despite multimodal standard-of-care therapy. One of the major challenges for effective treatment of these tumors is their high heterogeneity, which stems, in part, from differences in the cell of origin. Using a CNP-Cre transgenic mouse model, this study investigates the role of differentiated oligodendrocytes as a candidate cell of origin for GBM. We show that these cells can give rise to GBM tumors when targeted with Cre-inducible oncogenic lentiviral vectors. Notably, in mice these oligodendrocyte-derived GBM tumors lead to early-onset motor deficits that are not observed in neuron-derived tumors. In addition, these tumors exhibit a distinct transcriptional profile involving altered expression of myelin-related genes, emphasizing the impact of the cell of origin on both molecular and behavioral phenotypes of GBM. We believe that a deeper understanding of the identity of the cell of origin may contribute to uncovering new mechanisms and therapeutic vulnerabilities in GBM.