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; Samuel H. Cheshier

doi:10.1038/s41467-018-06564-9

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. TaylorIrving L. Weissman, Siddhartha S. Mitra, Samuel H. Cheshier

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	English (US)
Article number	4121
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06564-9
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kahn, S. A., Wang, X., Nitta, R. T., Gholamin, S., Theruvath, J., Hutter, G., Azad, T. D., Wadi, L., Bolin, S., Ramaswamy, V., Esparza, R., Liu, K. W., Edwards, M., Swartling, F. J., Sahoo, D., Li, G., Wechsler-Reya, R. J., Reimand, J., Cho, Y. J., ... Cheshier, S. H. (2018). Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nature communications, 9(1), Article 4121. https://doi.org/10.1038/s41467-018-06564-9

Kahn, SA, Wang, X, Nitta, RT, Gholamin, S, Theruvath, J, Hutter, G, Azad, TD, Wadi, L, Bolin, S, Ramaswamy, V, Esparza, R, Liu, KW, Edwards, M, Swartling, FJ, Sahoo, D, Li, G, Wechsler-Reya, RJ, Reimand, J, Cho, YJ, Taylor, MD, Weissman, IL, Mitra, SS & Cheshier, SH 2018, 'Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma', Nature communications, vol. 9, no. 1, 4121. https://doi.org/10.1038/s41467-018-06564-9

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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.",

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AU - Theruvath, Johanna

AU - Hutter, Gregor

AU - Azad, Tej D.

AU - Wadi, Lina

AU - Bolin, Sara

AU - Ramaswamy, Vijay

AU - Esparza, Rogelio

AU - Liu, Kun Wei

AU - Edwards, Michael

AU - Swartling, Fredrik J.

AU - Sahoo, Debashis

AU - Li, Gordon

AU - Wechsler-Reya, Robert J.

AU - Reimand, Jüri

AU - Cho, Yoon Jae

AU - Taylor, Michael D.

AU - Weissman, Irving L.

AU - Mitra, Siddhartha S.

AU - Cheshier, Samuel H.

PY - 2018/12/1

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N2 - 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.

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

Abstract

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