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.
Highlights
Cancer Institute, University of Utah, 100 North Mario Capecchi Drive Suite 3850, Salt Lake City, Utah 84113, USA
After confirmation of tumor growth and metastasis by bioluminescent imaging (Fig. 1b), we determined the relative expression of surface NOTCH1 as well as the transcriptionally active NOTCH1 intracellular domain (NICD1) between tumor tissues isolated from primary cerebellar site and metastatic spinal tumor site
We found higher frequencies of cells expressing surface NOTCH1 in tumor cells isolated from spinal metastases compared with tumor cells from the primary tumor sites in all xenografts analyzed (Fig. 1c, d and Supplementary Fig. 1)
Summary
Cancer Institute, University of Utah, 100 North Mario Capecchi Drive Suite 3850, Salt Lake City, Utah 84113, USA. NICD1 expression, the active form of NOTCH1, was fivefold to tenfold higher in tumor cells from spinal metastases compared with cells from primary tumor sites (Fig. 1e, f). In a spontaneous MYCN-driven transgenic medulloblastoma mouse model (GTML)[9], the primary tumor was negative for activated Notch[1] and Hes[1], whereas both markers were present in the spinal metastasis (Supplementary Fig. 2d).
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