Beckmann PJ, Larson JD, Larsson AT, Ostergaard JP, Wagner S, Rahrmann EP, Shamsan GA, Otto GM, Williams RL, Wang J, Lee C, Tschida BR, Das P, Dubuc AM, Moriarity BS, Picard D, Wu X, Rodriguez FJ, Rosemarie Q, Krebs RD, Molan AM, Demer AM, Frees MM, Rizzardi AE, Schmechel SC, Eberhart CG, Jenkins RB, Wechsler-Reya RJ, Odde DJ, Huang A, Taylor MD, Sarver AL, and Largaespada DA
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., (©2019 American Association for Cancer Research.)