Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors
| Autor: | Michelle M. Frees, George Maxwell Otto, Sandra Wagner, David J. Odde, David A. Largaespada, Paramita Das, Pauline J. Beckmann, Rory L. Williams, Barbara R. Tschida, Robert B. Jenkins, Alex T. Larsson, Stephen C Schmechel, Quincy Rosemarie, Jon D. Larson, Charles G. Eberhart, Fausto J. Rodriguez, Eric P. Rahrmann, Xiaochong Wu, Jason Ostergaard, Jun Wang, Addison M. Demer, Michael D. Taylor, Daniel Picard, Adrian M. Dubuc, Ryan D Krebs, Catherine Lee, Annie Huang, Aaron L. Sarver, Robert J. Wechsler-Reya, Branden S. Moriarity, Anthony E. Rizzardi, Amy M. Molan, Ghaidan Shamsan |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Medulloblastoma Cancer Research Mutagenesis (molecular biology technique) Biology medicine.disease medicine.disease_cause Article nervous system diseases Insertional mutagenesis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Neuroblastoma medicine Cancer research biology.protein Transposon mutagenesis Sonic hedgehog Carcinogenesis neoplasms Gene |
| Zdroj: | Cancer Research. 79:905-917 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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