Nature communications · 2024
Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Mbah Nneka E, Myers Amy L, Sajjakulnukit Peter, Chung Chan, Thompson Joyce K, Hong Hanna S, Giza Heather, Dang Derek, Nwosu Zeribe C, Shan Mengrou, Sweha Stefan R, Maydan Daniella D, Chen Brandon, Zhang Li, Magnuson Brian, Zhu Zirui, Radyk Megan, Lavoie Brooke, Yadav Viveka Nand, Koo Imhoi, Patterson Andrew D, Wahl Daniel R, Franchi Luigi, Agnihotri Sameer, Koschmann Carl J, Venneti Sriram, Lyssiotis Costas A
Аннотация
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.