<i>Sleeping Beauty</i> Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Pauline J. Beckmann(University of Minnesota Medical Center), Jon D. Larson(University of Minnesota Medical Center), Alex T. Larsson(University of Minnesota Medical Center), Jason Ostergaard(University of Minnesota Medical Center), Sandra Wagner(University of Minnesota Medical Center), Eric P. Rahrmann(Cancer Research UK Cambridge Center), Ghaidan A. Shamsan(University of Minnesota), George M. Otto(University of Minnesota Medical Center), Rory L. Williams(California Institute of Technology), Jun Wang(Discovery Institute), Catherine Lee(Discovery Institute), Barbara R. Tschida(University of Minnesota Medical Center), Paramita Das(University of Minnesota Medical Center), Adrian M. Dubuc(Brigham and Women's Hospital), Branden S. Moriarity(University of Minnesota Medical Center), Daniel Picard(German Cancer Research Center), Xiaochong Wu(Brain Tumour Research), Fausto J. Rodríguez(Johns Hopkins Hospital), Quincy Rosemarie(University of Wisconsin–Madison), Ryan D. Krebs(University of Minnesota Medical Center), Amy M. Molan(University of Minnesota), Addison M. Demer(University of Minnesota Medical Center), Michelle M. Frees(University of Minnesota Medical Center), Anthony E. Rizzardi(University of Minnesota), Stephen C. Schmechel(University of Minnesota), Charles G. Eberhart(Johns Hopkins University), Robert B. Jenkins(Mayo Clinic), Robert J. Wechsler‐Reya(Discovery Institute), David J. Odde(University of Minnesota), Annie Huang(Hospital for Sick Children), Michael D. Taylor(Brain Tumour Research), Aaron L. Sarver(University of Minnesota Medical Center), David A. Largaespada(University of Minnesota Medical Center)
Cancer Research
January 23, 2019
10.1158/0008-5472.can-18-1261
Cited by 52Open Access
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Abstract

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.

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