Abstract：
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
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,Demdoi
10.1158/0008-5472.CAN-18-1261subject
Has Abstractpub_date
2019-03-01 00:00:00pages
905-917issue
5eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-18-1261journal_volume
79pub_type
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