Heterogeneity and excitability of BRAF(V600E)-induced tumors is determined by Akt/mTOR-signaling state and Trp53-loss

BACKGROUND: Developmental brain tumors harboring BRAF(V600E) somatic mutation are diverse. Here, we describe molecular factors that determine BRAF(V600E)-induced tumor biology and function. METHODS: Intraventricular in utero electroporation in combination with the piggyBac transposon system was utilized to generate developmental brain neoplasms, which were comprehensively analyzed with regard to growth using near-infrared in-vivo imaging, transcript signatures by RNA sequencing, and neuronal activity by multielectrode arrays. RESULTS: BRAF (V600E) expression in murine neural progenitors elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG) only in concert with active Akt/mTOR-signaling. Purely glial tumors resembling aspects of polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAF(V600E) alone. Additional somatic Trp53-loss is sufficient to generate anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAF(V600E)/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter. CONCLUSION: mTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAF(V600E)-induced tumors.