TY - JOUR
T1 - Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors
AU - Beckmann, Pauline J.
AU - Larson, Jon D.
AU - Larsson, Alex T.
AU - Ostergaard, Jason P.
AU - Wagner, Sandra
AU - Rahrmann, Eric P.
AU - Shamsan, Ghaidan A.
AU - Otto, George M.
AU - Williams, Rory L.
AU - Wang, Jun
AU - Lee, Catherine
AU - Tschida, Barbara R.
AU - Das, Paramita
AU - Dubuc, Adrian M.
AU - Moriarity, Branden S.
AU - Picard, Daniel
AU - Wu, Xiaochong
AU - Rodriguez, Fausto J.
AU - Rosemarie, Quincy
AU - Krebs, Ryan D.
AU - Molan, Amy M.
AU - Demer, Addison M.
AU - Frees, Michelle M.
AU - Rizzardi, Anthony E.
AU - Schmechel, Stephen C.
AU - Eberhart, Charles G.
AU - Jenkins, Robert B.
AU - Wechsler-Reya, Robert J.
AU - Odde, David J.
AU - Huang, Annie
AU - Taylor, Michael D.
AU - Sarver, Aaron L.
AU - Largaespada, David A.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-18-1261
DO - 10.1158/0008-5472.CAN-18-1261
M3 - Article
C2 - 30674530
AN - SCOPUS:85062288132
SN - 0008-5472
VL - 79
SP - 905
EP - 917
JO - Cancer research
JF - Cancer research
IS - 5
ER -