N-myc mediated translation control is a therapeutic vulnerability in medulloblastoma

Deregulation of N-myc is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data unexpectedly revealed that N-myc regulates the expression of specific components (~5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic. Overall design: Cells were originated from our germline genetically engineered mouse model (GEMM) for MYCN-driven medulloblastoma (GLT1-TRE-MYCN/Luciferase-GTML), in which a human MYCN transgene was targeted to murine hindbrain neural progenitor cells (Swartling et al., 2010). Medulloblastoma cells were treated for three hours with the ATP-site inhibitor Rapalink-1, which blocks the two translation arms, ribosomal protein S6 kinase (S6K) and eIF4E cap-binding protein downstream of mTORC1; or rapamycin, an allosteric inhibitor that blocks S6K but not eIF4E signaling. Three replicates were used for each condition. Genome-wide ribosome profiling was performed.