Document Type
Article
Publication Date
10-17-2024
Identifier
DOI: 10.1038/s41467-024-52973-4; PMCID: PMC11487135
Abstract
H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
Journal Title
Nat Commun
Volume
15
Issue
1
First Page
8983
Last Page
8983
MeSH Keywords
Humans; Animals; Cell Differentiation; Oxidative Phosphorylation; Mice; Cell Line, Tumor; Glioma; Astrocytes; Oligodendroglia; Mitochondria; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Brain Neoplasms; Xenograft Model Antitumor Assays
Keywords
Cell Differentiation; Oxidative Phosphorylation; Tumor Cell Line; Glioma; Astrocytes; Oligodendroglia; Mitochondria; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Brain Neoplasms; Xenograft Model Antitumor Assays
Recommended Citation
Mbah NE, Myers AL, Sajjakulnukit P, et al. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nat Commun. 2024;15(1):8983. Published 2024 Oct 17. doi:10.1038/s41467-024-52973-4
Comments
Grants and funding
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Publisher's Link: https://www.nature.com/articles/s41467-024-52973-4