Journal Article

Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma

Koschmann, Carl J., Zhu, Zirui, Mbah, Nneka E., Koo, Imhoi, Sweha, Stefan R., Patterson, Andrew D., Radyk, Megan, Magnuson, Brian, Lyssiotis, Costas A., Sajjakulnukit, Peter, Nwosu, Zeribe C., Giza, Heather, Dang, Derek, Wahl, Daniel R., Zhang, Li, Myers, Amy L., Yadav, Viveka Nand, Agnihotri, Sameer, Shan, Mengrou, Hong, Hanna S., Chen, Brandon, Venneti, Sriram, Lavoie, Brooke, Franchi, Luigi, Thompson, Joyce K., Maydan, Daniella D., Chung, Chan

2024

Overview

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. Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 38 / 59 / 631/67/2327 / 631/67/2329 / 631/67/2332 / Animals / Astrocytes - drug effects / Astrocytes - metabolism / Biosynthesis / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Brain Stem Neoplasms - drug therapy / Brain Stem Neoplasms - genetics / Brain Stem Neoplasms - metabolism / Brain Stem Neoplasms - pathology / Brain tumors / Cell culture / Cell death / Cell differentiation / Cell Differentiation - drug effects / Cell Line, Tumor / Cholesterol / Diffuse Intrinsic Pontine Glioma - drug therapy / Diffuse Intrinsic Pontine Glioma - genetics / Diffuse Intrinsic Pontine Glioma - metabolism / Diffuse Intrinsic Pontine Glioma - pathology / Glial stem cells / Glioma / Glioma - drug therapy / Glioma - genetics / Glioma - metabolism / Glioma - pathology / Heterogeneity / Humanities and Social Sciences / Humans / Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology / Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use / Metabolism / Metabolomics / Mice / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Oligodendroglia - drug effects / Oligodendroglia - metabolism / Oligodendroglia - pathology / Oxidative phosphorylation / Oxidative Phosphorylation - drug effects / Pediatrics / Phenotypes / Phosphorylation / Science / Science (multidisciplinary) / Statins / Stem cells / Therapeutic targets / Transcriptomics / Xenograft Model Antitumor Assays