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Nat Commun. 2018 Oct 8;9(1):4121. doi: 10.1038/s41467-018-06564-9.

Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.

Author information

1
Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, 94305, California, USA. suzanakahn@gmail.com.
2
Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, 94305, California, USA. suzanakahn@gmail.com.
3
Department of Neurosurgery, Stanford University School of Medicine, Stanford, 94305, California, USA. suzanakahn@gmail.com.
4
Ludwig Institute for Cancer Research, Stanford University School of Medicine, Stanford, 94305, California, USA. suzanakahn@gmail.com.
5
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, M5G 0A4, Ontario, Canada.
6
Department of Neurosurgery, Stanford University School of Medicine, Stanford, 94305, California, USA.
7
Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, 94305, California, USA.
8
Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, 94305, California, USA.
9
Computational Biology Program, Ontario Institute for Cancer Research, Toronto, M5G 0A3, Ontario, Canada.
10
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, 75185, Sweden.
11
Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, 2880 Torrey Pines Scenic Drive, La Jolla, California, 92037, USA.
12
Ludwig Institute for Cancer Research, Stanford University School of Medicine, Stanford, 94305, California, USA.
13
Department of Pediatrics and Department of Computer Science and Engineering, University of California San Diego, San Diego, 92093, California, USA.
14
Department of Medical Biophysics, University of Toronto, Toronto, M5G 1L7, Ontario, Canada.
15
Department of Pediatrics, Children's Hospital Colorado, University of Colorado, School of Medicine, Room No. P18-4114, Research Complex 1-North MS-8302, 12800 East 19th Avenue, Aurora, Colorado, 80045, USA.
16
Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, 94305, California, USA. samuel.cheshier@hsc.utah.edu.
17
Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University School of Medicine, Stanford, 94305, California, USA. samuel.cheshier@hsc.utah.edu.
18
Department of Neurosurgery, Stanford University School of Medicine, Stanford, 94305, California, USA. samuel.cheshier@hsc.utah.edu.
19
Ludwig Institute for Cancer Research, Stanford University School of Medicine, Stanford, 94305, California, USA. samuel.cheshier@hsc.utah.edu.
20
Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children's Hospital and Huntsman Cancer Institute, University of Utah, 100 North Mario Capecchi Drive Suite 3850, Salt Lake City, Utah, 84113, USA. samuel.cheshier@hsc.utah.edu.

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

PMID:
30297829
PMCID:
PMC6175869
DOI:
10.1038/s41467-018-06564-9
[Indexed for MEDLINE]
Free PMC Article

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