MODL-16. SOMATICALLY ENGINEERED MOUSE MODELS RECAPITULATING CELLULAR AND MOLECULAR FEATURES OF HUMAN GBM

Abstract INTRODUCTION Mouse models are instrumental in advancing our understanding of glioblastoma (GBM), however many commonly used have features that limit their practicality or applicability. These limitations can include an incomplete immune context, a requirement for complex breeding strategies, high cost specialized lines, and unpredictability where tumors arise. We sought to develop validate mouse modeling system some the major human GBM subtypes overcame these practical challenges. METHODS In vivo electroporation was introduce genetic alterations into periventricular cells early postnatal C57Bl6/j mice. PiggyBac transposon/transposase CRISPR-Cas9 systems were overexpress (OE) knock out (KO) genes associated with mesenchymal (Nf1-KO/Pten-KO/p53-KO), classical (EGFRvIII-OE/Cdkn2a-KO/Pten-KO), proneural (Pdgfra-OE/Cdk4-OE/p53-KO) IDH-WT subtypes. KO OE confirmed by Indel Detection Amplicon Analysis immunofluorescent staining (IF). Tumours analyzed histologic, immunohistochemical, transcriptional (RNAseq) features. RESULTS Tumors arose near complete penetrance median survivals 36 116 days amongst models. All GFAP-expressing high-grade gliomas, distinct phenotypes different combinations. Nf1-KO/Pten-KO/p53-KO composed spindle cells. EGFRvIII-OE/Cdkn2a-KO/Pten-KO Pdgfra-OE/Cdk4-OE/p53-KO showed prevalence small, round Molecularly, enriched signature displayed more differentiated phenotype. The model also increased stromal macrophages. other had mixed profiles OPC- NPC-like gene signatures found GBM. Once formed, from each transplantable mice generate subsequent tumors. CONCLUSION developed validated rapid, versatile, reproducible GBMs. allow controlled study pathogenesis, progression, treatment response, robust generation syngeneic implantable serve as valuable tools preclinical testing.