Pathogenetic insights from novel mouse models for human epilepsy-associated developmental glioneuronal tumors

Abstract

<strong>Background: </strong> Developmental, biologically benign brain tumors associated with epilepsy represent a highly heterogeneous group of neoplasms and include glioneuronal and glial entities. Gangliogliomas (GGs) are most abundant in this group. <em>BRAF^V600E</em> is highly frequent in GGs and activation of mTOR cascade signaling has been reported. Occasional malignant GG variants harbor mutated <em>TP53</em>. The improved understanding of the genetic basis and molecular alterations of developmental epilepsy associated brain tumors in concert with the availability of new transgenic techniques and large-scale omics approaches allows the integrated analyses of pathomechanisms of these neoplasms systematically in novel mouse models. <br /> <strong>Aims: </strong> Thus, the present study aims to (1) develop and characterize in vivo tumor models for GGs recapitulating glioneuronal- and epilepsy-associated features, (2) understand their subsequent histogenesis and cellular composition, and (3) gain knowledge on mechanisms associated with altered excitability. <br /> <strong>Results: </strong> The present data show that co-electroporation of the constitutively active Akt and mutant <em>BRAF^V600E</em> transgenes in mouse neural precursors is required to induce lowgrade glioneuronal tumors, resembling histopathological features of human GGs including strong microglial infiltrates. These neoplasms arise clonally from a single precursor population, still capable to develop both neuronal and glial cells. Interestingly, the presence of only one transgene does not lead to GG development. Moreover, <em>Trp53</em> deletion in this model leads to high-grade glioneuronal tumors with a more severe clinical outcome. Purely glial tumors resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from only <em>BRAF^V600E</em>. Spontaneous spike evaluation reflected the highest intrinsic activity potential by tumors harboring both <em>BRAF^V600E</em> and mTOR activation. <br /> <strong>Conclusion: </strong> The combinatorial genetic architecture of <em>BRAF^V600E</em> induced developmental brain tumors with PI3K/Akt/mTOR signaling and <em>Trp53</em>-loss determines not only the neuropathological characteristics but also key biological as well as functional features with implication for improving the clinical management of affected patients.