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

Nneka E. Mbah, Amy L. Myers, Peter Sajjakulnukit, Chan Chung, Joyce K. Thompson, Hanna S. Hong, Heather Giza, Derek Dang, Zeribe C. Nwosu, Mengrou Shan, Stefan R. Sweha, Daniella D. Maydan, Brandon Chen, Li Zhang, Brian Magnuson, Zirui Zhu, Megan Radyk, Brooke Lavoie, Viveka Nand Yadav, Imhoi Koo, Andrew D. Patterson, Daniel R. Wahl, Luigi Franchi, Sameer Agnihotri, Carl J. Koschmann, Sriram Venneti () and Costas A. Lyssiotis ()
Additional contact information
Nneka E. Mbah: University of Michigan
Amy L. Myers: University of Michigan
Peter Sajjakulnukit: University of Michigan
Chan Chung: University of Michigan
Joyce K. Thompson: University of Michigan
Hanna S. Hong: University of Michigan
Heather Giza: University of Michigan
Derek Dang: University of Michigan
Zeribe C. Nwosu: University of Michigan
Mengrou Shan: University of Michigan
Stefan R. Sweha: University of Michigan
Daniella D. Maydan: University of Michigan
Brandon Chen: University of Michigan
Li Zhang: University of Michigan
Brian Magnuson: University of Michigan
Zirui Zhu: University of Michigan
Megan Radyk: University of Michigan
Brooke Lavoie: University of Michigan
Viveka Nand Yadav: Children’s Mercy Research Institute (CMRI)
Imhoi Koo: Pennsylvania State University
Andrew D. Patterson: the Pennsylvania State University
Daniel R. Wahl: University of Michigan
Luigi Franchi: University of Michigan Medical School
Sameer Agnihotri: University of Pittsburgh Hillman Cancer Center
Carl J. Koschmann: University of Michigan
Sriram Venneti: University of Michigan
Costas A. Lyssiotis: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52973-4

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