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

Suzana A. Kahn (), Xin Wang, Ryan T. Nitta, Sharareh Gholamin, Johanna Theruvath, Gregor Hutter, Tej D. Azad, Lina Wadi, Sara Bolin, Vijay Ramaswamy, Rogelio Esparza, Kun-Wei Liu, Michael Edwards, Fredrik J. Swartling, Debashis Sahoo, Gordon Li, Robert J. Wechsler-Reya, Jüri Reimand, Yoon-Jae Cho, Michael D. Taylor, Irving L. Weissman, Siddhartha S. Mitra and Samuel H. Cheshier ()
Additional contact information
Suzana A. Kahn: Stanford University School of Medicine
Xin Wang: University of Toronto
Ryan T. Nitta: Stanford University School of Medicine
Sharareh Gholamin: Stanford University School of Medicine
Johanna Theruvath: Stanford University School of Medicine
Gregor Hutter: Stanford University School of Medicine
Tej D. Azad: Stanford University School of Medicine
Lina Wadi: Ontario Institute for Cancer Research
Sara Bolin: Stanford University School of Medicine
Vijay Ramaswamy: University of Toronto
Rogelio Esparza: Stanford University School of Medicine
Kun-Wei Liu: Sanford Burnham Prebys Medical Discovery Institute
Michael Edwards: Stanford University School of Medicine
Fredrik J. Swartling: Uppsala University
Debashis Sahoo: University of California San Diego
Gordon Li: Stanford University School of Medicine
Robert J. Wechsler-Reya: Sanford Burnham Prebys Medical Discovery Institute
Jüri Reimand: Ontario Institute for Cancer Research
Yoon-Jae Cho: Stanford University School of Medicine
Michael D. Taylor: University of Toronto
Irving L. Weissman: Stanford University School of Medicine
Siddhartha S. Mitra: Stanford University School of Medicine
Samuel H. Cheshier: Stanford University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06564-9

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