Heterogeneity and excitability of BRAFV600E-induced tumors is determined by PI3K/mTOR-signaling state and Trp53-loss

Abstract

AbstractBackgroundDevelopmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function.MethodsIntraventricular in utero electroporation in combination with the piggyBac transposon system is employed as a tool to generate developmental brain neoplasms. In vivo tumor growth is monitored by using the infrared fluorescent protein (iRFP). Lineage inference is carried out by using the Brainbow transgene. Neural activity from tumor slices is assessed by multielectrode array. RNA sequencing is exploited to analyze the induced neoplasms at the transcriptomic level.ResultsBRAFV600E in murine neural progenitors only in concert with active PI3K/mTOR-signaling through constitutively phosphorylated Akt-kinase (pAkt) elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG). Purely glial tumors partially resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to induce anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/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.ConclusionmTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors.Key pointsIUE of BRAFV600E and activation of mTOR leads to ganglioglioma (GG)-like tumors, while BRAFV600E alone give rise to PLNTY-like neoplasms.Anaplastic GGs depend on the Trp53 deletion in combination to BRAFV600E and PI3K-mTOR signaling cascade.Importance of the StudyGlioneuronal tumors are challenging with respect to biological behavior and seizure emergence. While BRAFV600E in murine neural precursors induces oligoid tumors, it requires an overactivation of PI3K/mTOR-signaling for the development of hyperexcitable gangliogliomas and additional Trp53-loss for anaplastic transformation.