Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma
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.
Authors
- Peter Sajjakulnukit (ORCID: https://orcid.org/0000-0002-8556-7481)
- Carl Koschmann (ORCID: https://orcid.org/0000-0002-0825-7615)
- Imhoi Koo (ORCID: https://orcid.org/0000-0002-5816-0627)
- Heather Giza
- Derek Dang (ORCID: https://orcid.org/0000-0003-2071-4898)
- Sriram Venneti (ORCID: https://orcid.org/0000-0001-9764-0423)
- Megan D. Radyk (ORCID: https://orcid.org/0000-0002-3660-2906)
- Hanna S. Hong (ORCID: https://orcid.org/0000-0003-1202-2808)
- Joyce K. Thompson (ORCID: https://orcid.org/0000-0001-7898-0078)
- Daniel Wahl (ORCID: https://orcid.org/0000-0001-9894-5085)
- Zeribe C. Nwosu (ORCID: https://orcid.org/0000-0003-1641-2045)
- Amy L. Myers
- Brian Magnuson (ORCID: https://orcid.org/0000-0002-5301-3302)
- Sameer Agnihotri (ORCID: https://orcid.org/0000-0001-6584-3795)
- Nneka E. Mbah
- Stefan R. Sweha (ORCID: https://orcid.org/0000-0002-1807-6770)
- Andrew D. Patterson (ORCID: https://orcid.org/0000-0003-2073-0070)
- Chan Chung (ORCID: https://orcid.org/0000-0003-0510-8996)
- Luigi Franchi
- Viveka Nand Yadav (ORCID: https://orcid.org/0009-0001-5354-3717)
- Mengrou Shan (ORCID: https://orcid.org/0000-0001-6385-9064)
- Costas Andreas Lyssiotis (ORCID: https://orcid.org/0000-0001-9309-6141)
- Brandon Chen (ORCID: https://orcid.org/0000-0002-6319-2228)
- Daniella D. Maydan
- Li Zhang (ORCID: https://orcid.org/0000-0002-0703-7506)
- Zirui Zhu (ORCID: https://orcid.org/0000-0003-4008-6518)
- Brooke Lavoie
Institutions
- Pennsylvania State University (US)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- University of Michigan (US)
- Brain Tumour Research (GB)
- Michigan Medicine (US)
- Michigan Center for Translational Pathology (US)
- UPMC Hillman Cancer Center (US)
- Mercy Research (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1038/s41467-024-52973-4
- Citations
- 17
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 7.45
Funders
- U.S. Department of Defense
- Alex's Lemonade Stand Foundation for Childhood Cancer
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke