PM-08 * INVESTIGATING THE DETERMINANTS OF GBM SUBTYPES USING NOVEL MOUSE MODELS

Abstract

Molecular characterization of glioblastoma multiforme (gbm) has shown adult gbms to comprise a number of subtypes based on their gene expression signatures. While these subtypes are somewhat associated with distinct genetic alterations, the relative contributions of oncogenic driver, cell of origin and developmental stage are not fully understood. Using a novel and highly versatile modeling platform based on in vivo electroporation mediated transfer of transposon based plasmids to ventricular neural progenitors, we have generated high grade gliomas in mice using PDGFA, EGFRVIII or RasV12 expression in combination with p53 loss. These tumours show complete penetrance by 5 weeks post electroporation and bear key features of gbm such as necrosis and prevalent vascularisation. Gene expression analysis by Nanostring and subsequent unsupervised clustering shows each oncogenic driver to result in tumours of distinct gene expression profiles, with the PDGFA and RasV12 driven tumours showing similarity to the proneural and mesenchymal subclasses respectively. Modification of our plasmid system to incorporate selective promoters, floxed stop cassettes and tamoxifen inducible cre recombinase grants us precise spatiotemporal control over induction of gliomagenesis and allows us to probe the influence of developmental stage, cell of origin, brain region and gene expression level to the resulting tumour gene expression profiles.