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Cancer Res. 2019 Mar 1;79(5):905-917. doi: 10.1158/0008-5472.CAN-18-1261. Epub 2019 Jan 23.

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

Author information

1
Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota.
2
Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, England, United Kingdom.
3
Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
4
Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California.
5
Department of Bioengineering, California Institute of Technology, Pasadena, California.
6
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
7
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
8
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
9
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
10
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
11
Division of Neuropathology, Johns Hopkins Hospital, Baltimore, Maryland.
12
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.
13
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
14
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
15
Department of Clinical Sciences, College of Medicine, Florida State University, Sarasota, Florida.
16
Department of Pathology, Ophthalmology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
17
Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, 200 First Street Southwest, Rochester, Minnesota.
18
Division of Hematology, The Hospital for Sick Children, Toronto, Ontario, Canada.
19
Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota. larga002@umn.edu.

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.

PMID:
30674530
PMCID:
PMC6397665
[Available on 2020-03-01]
DOI:
10.1158/0008-5472.CAN-18-1261

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