TMOD-44. HGF-AUTOCRINE ACTIVATION OF MET RECEPTOR TYROSINE KINASE INDUCES DE NOVO GLIOMA FORMATION IN MICE

Genomic profiling of glioblastoma (GBM) has identified 4 molecular classifications, with the mesenchymal subtype as the most invasive phenotype resulting in short survival. The Met oncogene activation leads to invasive tumor growth and is a mesenchymal marker. Within the same GBMs, elevated MET activation is often accompanied by an increased expression of hepatocyte growth factor (HGF), suggesting a ligand-dependent activation of MET via an HGF-autocrine loop formation. While HGF-autocrine activation is considered a molecular feature determining the vulnerability to MET inhibitors, whether it is causal to glioma initiation is elusive. In this study, using a well-established Sleeping Beauty transposon strategy, we show that mixed injection of human Hgf and Met DNA together with a short hairpin siRNA against p53 into the lateral ventricle of neonatal mice results in de novo glioma formation with invasive phenotypes that resembles human GBM pathology. While neural stem cells (NSC) are hypothetically considered the cell of origin of GBM, the glioma spheres harvested from the tumor models expressed nestin, GFAP, and Sox 2, the markers of NSCs. When transplanted, these neurosphere cells also initiated tumors in mice that were suppressed by a MET small molecule inhibitor. Our results suggest that constitutively MET activation by HGF-autocrine loop may transform NSCs into glioma initiating cells that ultimately result in GBM formation. While Met inhibitors are being evaluated in clinical trials against multiple cancer types, our genetically engineered glioma mouse model driven by human HGF-autocrine activation (SB-hHgf/Met) provides a great tool for studying GBM tumor biology and MET targeting therapeutics.