BRAFV600E interacts with mTOR pathway activation and Trp53 loss in mouse neural progenitors in inducing diverse dysplastic glioneuronal tumors

Silvia Cases-Cunillera1, Karen M. J. Van Loo1, Sugirthan Sivalingam2, Johannes Schwerdt1, Hartmut Vatter3, Susanne Schoch1, Albert J. Becker1

1 Section for Translational Epilepsy Research, Department of Neuropathology
2 Department of Human Genetics
3 Department of Neurosurgery

BRAFV600E-mutations are encountered in a substantial fraction of gangliogliomas (GGs), the most frequent pediatric glioneuronal tumors. BRAFV600Epositively correlates with phosphorylated (p)S6 as surrogate marker for mTOR pathway activation in human GGs. In contrast, expression of the mouseequivalent BRAFV637Ein neural precursors was sufficient to induce glioneuronal tumors but did not result in increased pS6-levels in BRAFV637E-mutant neurons. Here, we demonstrate that intraventricularly in uteroelectroporation (IUE) of a vector encoding BRAFV600Eat embryonal day 14 gives rise to neurocytic lesions with increased pS6-expression that lack a neoplastic glial component. In contrast, co-IUE of BRAFV600Eand a constitutively active Akt-kinase (pAkt) results in benign tumors composed of large and often bi-nucleated neurons and neoplastic astroglia. mRNA sequencing of BRAFV600Eand BRAFV600E/pAkt tumor tissue revealed transcript signatures of the latter tumor to strongly reflect human BRAFV600E-positive GGs. Finally, we demonstrate that IUE of BRAFV600E/pAkt combined with somatic Trp53-loss is sufficient to induce anaplastic GGs. We provide a faithful GG-mouse model, which enables new insights into the molecular pathogenesis of major glioneuronal tumor variants and the exploration of perspective therapies.