PJ Beckmann, JD Larson, AT Larsson, JP Ostergaard, S Wagner, EP Rahrmann, GA Shamsan, GM Otto, RL Williams, J Wang, C Lee, BR Tschida, P Das, AM Dubuc, BS Moriarity, D Picard, X Wu, FJ Rodriguez, Q Rosemarie, RD Krebs, AM Molan, AM Demer, MM Frees, AE Rizzardi, SC Schmechel, CG Eberhart, RB Jenkins, RJ Wechsler-Reya, DJ Odde, A Huang, MD Taylor, AL Sarver, DA Largaespada
Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. SIGNIFICANCE: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.