Abstract 6041: Investigating metabolic dependencies of group 3 medulloblastoma

Abstract Medulloblastomas (MB) are the most common pediatric brain malignancy. Transcriptomic, genomic, and epigenomic insights have stratified these tumors into four distinct subtypes: SHH, WNT, Group 3 and Group 4. Of the four subtypes, Group 3 tumors bear the worst prognosis. Each MB subtype is distinguished by their unique transcriptome profile and epigenetic landscape. Metabolic reprogramming is a hallmark of cancer and allows cells to actively promote the utilization of nutrients to support their uncontrolled proliferation. We identified distinct transcriptional metabolic profiles in medulloblastomas. We found that Group 3 MB show upregulation of key anabolic pathways. We then cross-referenced these data from comprehensive single-cell RNA sequencing profiles of cerebellar developmental niches. We found that Group 3 MB exhibits metabolic signature similar that of early progenitors, rhombic lip progenitors, and cerebellar ventricular zone derivatives. Finally, we identify DLAT, the E2 subunit of the pyruvate dehydrogenase complex, as a uniquely upregulated gene in Group 3 MB. Knockdown of DLAT inhibited tumor growth in-vitro and in-vivo suggesting a potential targets for future therapeutic regimens. Citation Format: Derek Dang, Kyle S. Smith, Pooja Panwalkar, John McKolay, Olamide Animasahun, Abhinav Achreja, Deepak Nagrath, Paul A. Northcott, Sriram Venneti. Investigating metabolic dependencies of group 3 medulloblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6041.