MB-16
NOTCH1 PROMOTES GROUP 3 MEDULLOBLASTOMA METASTASIS, INITIATION AND SELF-RENEWAL Free

Medulloblastoma is the most common pediatric malignant brain. Group 3, the most aggressive molecular subgroup of medulloblastoma, arises in the cerebellum and/or floor of the 4^th ventricle and frequently disseminates through the cerebrospinal fluid (CSF) to different regions of the brain and spinal cord. The presence and stage of metastasis (tumor cells in the CSF and in the spinal subarachnoid space) are directly related to the overall survival and progression-free survival of medulloblastoma patients. The mechanisms of dissemination through the CSF are very poorly understood and the pathways involved in medulloblastoma maintenance are unknown. We show that Notch1 pathway regulates group 3 medulloblastoma metastasis, initiation and self-renewal. Notch1 expressing cells are not only the self-renewing group 3 medulloblastoma tumor initiating cells but also are the cells which initiate spinal metastasis. Group 3 medulloblastoma spinal metastasis present increased expression of Notch1 and modulation of Notch1 intracellular domain (NICD1) expression is directly related to medulloblastoma metastasis and survival rate of tumor-bearing mice. In addition, sorted Notch1-negative group 3 medulloblastoma cells were unable to produce detectable metastasis in the first passage in vivo and to generate primary tumors in the second passage in vivo, whereas Notch1-positive cells robustly formed brain tumors and spinal metastasis upon in vivo passages. These findings identify Notch1-positive cells as the medulloblastoma stem cells. Notch1 is a pivotal driver of group 3 medulloblastoma initiation and progression, supporting the development of therapies targeting this pathway.