N-myc-Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-01, Vol.83 (1), p.130-140
• Main Authors: Kuzuoglu-Ozturk, Duygu, Aksoy, Ozlem, Schmidt, Christin, Lea, Robin, Larson, Jon D, Phelps, Ryan R L, Nasholm, Nicole, Holt, Megan, Contreras, Adrian, Huang, Miller, Wong-Michalak, Shannon, Shao, Hao, Wechsler-Reya, Robert, Phillips, Joanna J, Gestwicki, Jason E, Ruggero, Davide, Weiss, William A
• Format: Article
• Language: English
• Subjects: Animals; Cerebellar Neoplasms - pathology; Child; Disease Models, Animal; Eukaryotic Initiation Factor-4E - genetics; Humans; Medulloblastoma - pathology; Mice; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-22-0945

Deregulation of neuroblastoma-derived myc (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 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. Translatome analysis in medulloblastoma shows that N-myc drives selective translation of transcripts that promote protein homeostasis and that represent new therapeutic vulnerabilities.