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Cell Stem Cell. 2019 Sep 5;25(3):433-446.e7. doi: 10.1016/j.stem.2019.05.013. Epub 2019 Jun 13.

Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.

Author information

1
Department of Neurology and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Institute of Cancer Research, Sutton, London SM2 5NG, UK; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
3
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada; Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
4
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
5
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
7
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
8
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
9
Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
10
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
11
Institute of Clinical Neurosciences, Level 1, Learning and Research Building, Southmead Hospital, University of Bristol, Bristol BS10 5NB, UK.
12
Institute for Research on Cancer and Aging, Nice UMR CNRS 7284 INSERM U1081 UNS/UCA, Nice, France.
13
Institut Bergonie & INSERM U1218, Universite de Bordeaux, 229 cours de l'Argonne, 33076 Bordeaux Cedex, France.
14
Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim and Hector Institut for Translational Brain Research (HITBR gGmbH), Mannheim, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
MRC Centre for Regenerative Medicine and Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK.
16
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
17
Division of Pediatric Neurology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA; Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
18
Departments of Neurological Surgery and Pathology, University of California, San Francisco, CA 94158, USA.
19
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada; Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
20
Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
21
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
22
Department of Neurology and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Pediatrics, Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: waweiss@gmail.com.

Abstract

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

KEYWORDS:

SHH; human pluripotent stem cells; medulloblastoma; neuroepithelial stem cells

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