Cell competition between pre-malignant Trp53,Nf1-null oligodendrocyte precursor cells (OPCs) and normal OPCs is a necessary driver of gliomagenesis that operates through Nf1-loss-mediated Ras-mTORC1 signaling to generate unique protein species via regulated RNA splicing and translation, and blocking this competition-specific signaling—either by strengthening normal OPCs or by inhibiting mTORC1 in mutant OPCs—prevents both pre-malignant expansion and malignant transformation in mouse models and is relevant to human glioblastomas where normal OPCs are specifically eliminated from tumor regions.

Malignant glioma is incurable. Using a mouse genetic mosaic system to generate sporadic Trp53,Nf1-null OPCs, we previously identified oligodendrocyte precursor cell (OPC) as a cell-of-origin of glioma. Here, we report that pre-malignant Trp53,Nf1-null OPCs outcompete wildtype counterparts during their expansion. Blocking competition by mutating/strengthening wildtype OPCs impeded both pre-malignant progression and malignant expansion of glioma.

“In-tissue” phosphoproteomic profiling revealed an enrichment of phosphopeptides related to RNA splicing and protein translation at the peak of cell competition, suggesting that competitiveness may stem from unique protein species. Among candidates was mTORC1, whose pharmacological inhibition or genetic disruption resulted in a loss of competitiveness in our mouse model. Finally, analysis of patient biopsies and interrogating the role of individual gliomagenic mutations in OPC competition supported its relevance in human gliomas. Together, these findings identified the driving role of competitive interactions among OPCs in gliomagenesis, and suggest unconventional therapeutic strategies to target this process.