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

BRAF^V600E-mutations are encountered in a substantial fraction of gangliogliomas (GGs), the most frequent pediatric glioneuronal tumors. BRAF^V600Epositively correlates with phosphorylated (p)S6 as surrogate marker for mTOR pathway activation in human GGs. In contrast, expression of the mouseequivalent BRAF^V637Ein neural precursors was sufficient to induce glioneuronal tumors but did not result in increased pS6-levels in BRAF^V637E-mutant neurons. Here, we demonstrate that intraventricularly in uteroelectroporation (IUE) of a vector encoding BRAF^V600Eat embryonal day 14 gives rise to neurocytic lesions with increased pS6-expression that lack a neoplastic glial component. In contrast, co-IUE of BRAF^V600Eand a constitutively active Akt-kinase (pAkt) results in benign tumors composed of large and often bi-nucleated neurons and neoplastic astroglia. mRNA sequencing of BRAF^V600Eand BRAF^V600E/pAkt tumor tissue revealed transcript signatures of the latter tumor to strongly reflect human BRAF^V600E-positive GGs. Finally, we demonstrate that IUE of BRAF^V600E/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.