Metabolic Control of Translation in Glioblastoma

ABSTRACT Glioblastoma represents the most common primary malignant brain tumor with a median survival of less than 2 years. Despite extensive molecular characterization, precision oncology has had little penetration in clinical neuro-oncology, suggesting that novel therapies are needed. Many cancers, including glioblastoma, display accelerated protein synthesis associated with upregulation of major oncogenic pathways, including RTK/RAS, PI3K/AKT, MYC and β-catenin/WNT. In preliminary studies, we find that increased translation is heterogeneously distributed between tumor cells. Translation is regulated by post-transcriptional modifications of transfer RNAs (tRNAs). The human genome encodes ~500 tRNAs that recognize 61 codons for 20 amino acids, on which more than 100 types of tRNA modifications have been identified. Dysregulation of tRNA modifications is prevalent in cancer and often leads to altered tRNA abundance or function, resulting in global or codon-biased translational reprogramming. We performed a CRISPR screen of tRNA regulators to reveal critical dependencies in glioblastoma. Preliminary results suggest that tRNA regulators that integrate metabolites may be critical to glioblastoma growth. Dietary restrictions have been proposed as oncologic interventions. For example, high levels of methionine are required for the growth of many cancers, and dietary methionine restriction enhances cancer treatment through one-carbon metabolic remodeling. To date, dietary interventions for glioblastoma treatment have not been successful, of which the most studied approach is the ketogenic diet, based on the hypothesis that glioblastoma cells cannot utilize ketones efficiently and must rely on glucose as primary energy source. However, response rates have varied in different trials, limiting effective clinical translation. We recently found that dietary lysine restriction inhibits tumor growth through epigenetic remodeling of endogenous immune responses in preclinical studies. Here, we propose to interrogate metabolic rewiring and the cellular response to microenvironmental nutrients to regulate cellular translation in glioblastoma to inform the development of effective dietary intervention strategies.