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 Arh-gap36, 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.
Bibliographical noteFunding Information:
This work was supported by UofMN Genomics Center, UofMN Biology Materials Procurements Network, Research Animal Resources, and University Imaging Centers that are supported by the NCI. Support for this research was provided by The American Cancer Society (Research Professor Award no. 123939 to D.A. Largaespada), the NIH (U54CA210190 to D.A. Largaespada and D.J. Odde; R01CA113636 to D.A. Largaespada; T32 T32GM113846 to P.J. Beckmann; R50-CA211249 to A.L. Sarver; T32 AI083196 to B.R. Tschida; T32CA009138 to J.D. Larson; and R01CA172986 to D.J. Odde), the Children's Cancer Research Fund, and the Hedberg Family Chair (all to D.A. Largaespada).