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.