Inhibition of neurotrophin receptor p75 intramembran proteolysis by gamma-secretase inhibitor reduces medulloblastoma spinal metastasis

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 p75NTR is a central regulator for glioma invasion. γ-secretase mediated processing of the p75NTR is a major contributor to the highly invasive nature of malignant gliomas. In this study we examine the p75NTR expression and processing in medulloblastoma cells. Results show that p75NTR is a critical regulator of medulloblastoma spinal metastasis. γ-secretase inhibitor, which blocks p75NTR proteolytic processing, significantly abrogates p75NTR induced medulloblastoma migration and invasion in vitro and in vivo. This data suggests that p75NTR is also an important therapeutic target for MB. γ-secretase inhibitor may be a potentially effective clinical application for the treatment of medulloblastoma spinal metastasis.

Research highlights
► p75NTR was endogenously highly expressed in most medulloblastoma cell lines.
► Expression of p75NTR increases migration and invasion in medulloblastoma cells.
► γ-secretase inhibitors impairs the invasive nature of genetically distinct medulloblastoma.