How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.cancer | cellular quiescence | cellular reactivation | mTOR signaling

These results suggest that cortical astrocytes can be transformed into GBM and that combined dysregulation of MAPK and PI3K signaling revert G1/S-defective astrocytes to a primitive gene expression state. This genetically-defined, immunocompetent model of proneural GBM will be useful for preclinical development of MAPK/PI3K-targeted, subtype-specific therapies.

Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.