Understanding the Role of eIF4E in Medulloblastoma

Background

Medulloblastoma (MB) is the most common malignant brain tumor in children. While approximately 75% of patients survive more than five years, survivors have significant neurocognitive and neuroendocrine disabilities. MB is comprised of four distinct molecular subgroups (WNT, SHH, Group 3 and Group 4) differing in mutational spectra, gene expression signatures and clinical features including outcome. The proto-oncogene MYCN drives SHH subtype medulloblastoma, and when amplified, also marks the most aggressive and lethal subtype of medulloblastoma. Since MYCN is undruggable, understanding mechanisms through which MYCN drives tumors promises to improve prognosis and quality of life for children with high-risk medulloblastoma. MYCN is a major regulator of translation control, and mTOR, a serine threonine kinase, represents a key node through which MYCN can potentially regulate translation. In unpublished data, the Weiss lab used genetic and pharmacological methods to identify a critical role for eIF4E (eukaryotic translation initiation factor 4E, an mTOR target and the major regulator of cap-dependent translation) in tumorigenesis at the nexus between MYCN and mTOR. In our MYCN-driven “GTML” mouse medulloblastoma model, heterozygosity for eIF4E leads to half the level of eIF4E protein. GTML mice heterozygous for eIF4E never develop tumors (unpublished).

Project Goal

In this proposal, we leverage the interaction between MYCN and eIF4E to identify downstream targets of eIF4E in MYCN-driven tumorigenesis. In particular, we will identify cancer targets whose abundance is regulated by translation rather than transcription (and would therefore be missed by RNAseq studies) and that impact the growth and development of medulloblastoma.