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Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
- Source :
-
Nature communications [Nat Commun] 2024 Oct 17; Vol. 15 (1), pp. 8983. Date of Electronic Publication: 2024 Oct 17. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Astrocytes metabolism
Astrocytes drug effects
Oligodendroglia metabolism
Oligodendroglia drug effects
Oligodendroglia pathology
Mitochondria metabolism
Mitochondria drug effects
Brain Stem Neoplasms metabolism
Brain Stem Neoplasms genetics
Brain Stem Neoplasms pathology
Brain Stem Neoplasms drug therapy
Diffuse Intrinsic Pontine Glioma metabolism
Diffuse Intrinsic Pontine Glioma drug therapy
Diffuse Intrinsic Pontine Glioma genetics
Diffuse Intrinsic Pontine Glioma pathology
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
Brain Neoplasms metabolism
Brain Neoplasms pathology
Brain Neoplasms drug therapy
Brain Neoplasms genetics
Xenograft Model Antitumor Assays
Cell Differentiation drug effects
Oxidative Phosphorylation drug effects
Glioma metabolism
Glioma pathology
Glioma genetics
Glioma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39419964
- Full Text :
- https://doi.org/10.1038/s41467-024-52973-4