Medulloblastoma (MB) is the most devastating and common pediatric brain tumor. Tumor cells invading into surrounding tissue and disseminating through cerebrospinal fluid make treatment extremely difficult. Identifying the mechanisms of MB cells is therefore imperative for the development of novel treatments. A research group demonstrated recently that the multifunctional signaling protein neurotrophin receptor p75(NTR) is a central regulator for glioma invasion. gamma-secretase mediated processing of the p75(NTR) is a major contributor to the highly invasive nature of malignant gliomas. In this study we examine the p75(NTR) expression and processing in medulloblastoma cells. Results show that p75(NTR) is a critical regulator of medulloblastoma spinal metastasis. gamma-secretase inhibitor, which blocks p75(NTR) proteolytic processing, significantly abrogates p75(NTR) induced medulloblastoma migration and invasion in vitro and in vivo. This data suggests that p75(NTR) is also an important therapeutic target for MB. gamma-secretase inhibitor may be a potentially effective clinical application for the treatment of medulloblastoma spinal metastasis. (C) 2010 Elsevier Inc. All rights reserved.