Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors.

Autor:	Beckmann PJ; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Larson JD; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Larsson AT; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Ostergaard JP; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Wagner S; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Rahrmann EP; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, England, United Kingdom., Shamsan GA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Otto GM; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California., Williams RL; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Department of Bioengineering, California Institute of Technology, Pasadena, California., Wang J; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Lee C; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Tschida BR; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Das P; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Dubuc AM; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Moriarity BS; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Picard D; Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany., Wu X; Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada., Rodriguez FJ; Division of Neuropathology, Johns Hopkins Hospital, Baltimore, Maryland., Rosemarie Q; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin., Krebs RD; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Molan AM; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota., Demer AM; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Frees MM; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Rizzardi AE; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota., Schmechel SC; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.; Department of Clinical Sciences, College of Medicine, Florida State University, Sarasota, Florida., Eberhart CG; Department of Pathology, Ophthalmology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland., Jenkins RB; Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, 200 First Street Southwest, Rochester, Minnesota., Wechsler-Reya RJ; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Odde DJ; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Huang A; Division of Hematology, The Hospital for Sick Children, Toronto, Ontario, Canada., Taylor MD; Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada., Sarver AL; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota., Largaespada DA; Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota. larga002@umn.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Mar 01; Vol. 79 (5), pp. 905-917. Date of Electronic Publication: 2019 Jan 23.
DOI:	10.1158/0008-5472.CAN-18-1261
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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