Srishti Rajeev

Helios Scholar

Medulloblastoma (MB), the most common pediatric brain tumor, affects approximately 500 children annually in the United States. Unfortunately, standard-of-care treatments such as radiation and chemotherapy often cause neurocognitive defects in patients. Difluoromethylornithine (DFMO), a polyamine biosynthesis inhibitor, is currently being explored as a low-toxic alternative treatment for pediatric tumors. Our studies have shown that both primary and established MB cell lines are sensitive to DFMO with a half-maximal inhibitory concentration (IC50). We also demonstrated DFMO treatment alters energy metabolism in the DAOY MB cell line. Such changes can be leveraged towards therapeutic monitoring. Extracellular vesicles (EVs) have emerged as a minimally invasive source of biomarkers to study cancer pathology. However, despite the critical role EVs play in cancer, their metabolome remains poorly understood. We hypothesize that metabolites in EVs can serve as biomarkers for monitoring DFMO induced changes to the cellular metabolome. To best understand molecular effects of DFMO, we treated the DAOY MB cell line with four-fold and sixteen-fold lower IC50 concentrations of DFMO, and conducted untargeted metabolomics on isolated EVs. The DAOY EV metabolome were rich in endogenous metabolites, which included phospholipids, fatty acids, and acyl carnitines. Upon DFMO treatment, 29 metabolites were differentially abundant (p < 0.05) in the EV metabolome. These metabolites were associated with energy metabolism and lipid metabolism pathways, which may reflect changes in the cells’ metabolic state. Notably, five of these metabolites were positively correlated between cell and EV metabolomes, highlighting their potential as biomarkers. Here, we successfully characterized the EV metabolome from MB cells, and identified DFMO-mediated metabolic changes in a dose-dependent manner. Further research is required to validate these observations, which may have profound implications for patient care.