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 | |
| State | Published - Dec 1 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. / Kahn, Suzana A.; Wang, Xin; Nitta, Ryan T.; Gholamin, Sharareh; Theruvath, Johanna; Hutter, Gregor; Azad, Tej D.; Wadi, Lina; Bolin, Sara; Ramaswamy, Vijay; Esparza, Rogelio; Liu, Kun Wei; Edwards, Michael; Swartling, Fredrik J.; Sahoo, Debashis; Li, Gordon; Wechsler-Reya, Robert J.; Reimand, Jüri; Cho, Yoon-Jae; Taylor, Michael D.; Weissman, Irving L.; Mitra, Siddhartha S.; Cheshier, Samuel H.
In: Nature communications, Vol. 9, No. 1, 4121, 01.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma
AU - Kahn, Suzana A.
AU - Wang, Xin
AU - Nitta, Ryan T.
AU - Gholamin, Sharareh
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
Y1 - 2018/12/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054593438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054593438&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06564-9
DO - 10.1038/s41467-018-06564-9
M3 - Article
C2 - 30297829
AN - SCOPUS:85054593438
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4121
ER -