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Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance
Masahiro Okada1, Bavani Subramaniam2, Baobao Geng3
1Department of Neurological Surgery, University of California, San Francisco, California, USA.
Background:
Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies.
Methods:
To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis were assessed in DMG primary cells.
Results:
We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulting in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets.
Conclusions:
These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.
Insights
Mitochondrial biogenesis drives resistance to imipridone ONC201 in diffuse midline glioma (DMG). Targeting mitochondrial pathways offers new therapeutic strategies for this pediatric brain tumor.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Imipridone ONC201 is an FDA-approved therapy for H3K27-altered diffuse midline glioma (DMG).
- Clinical responses to ONC201 are limited, necessitating identification of resistance mechanisms.
- Understanding tumor-intrinsic and microenvironmental factors is crucial for improving therapeutic strategies.
Purpose of the Study:
- To identify mechanisms of imipridone resistance in diffuse midline glioma.
- To define tumor-intrinsic and microenvironmental factors influencing sensitivity or resistance to imipridones.
- To uncover actionable therapeutic targets for improving clinical outcomes.
Main Methods:
- Single-nucleus RNA and open-chromatin sequencing on postmortem DMG tissues (N=22).
- Myeloid phenotyping (N=46) and mitochondrial copy-number analysis (N=19).
- Validation in DMG primary cells assessing imipridone sensitivity and synergy with mitochondrial biogenesis inhibitors.
Main Results:
- Imipridone treatment reduced mesenchymal transition and myeloid-derived suppressive cells.
- Resistant DMG tumors exhibited increased mitochondrial density, turnover, and membrane potential.
- Mitochondrial biogenesis and PPARGC1A were identified as resistance biomarkers and therapeutic targets.
Conclusions:
- Mitochondrial biogenesis is implicated as a key biomarker for imipridone resistance in DMG.
- Targeting mitochondrial biogenesis presents a promising strategy for combination therapies.
- These findings aim to improve therapeutic options for pediatric brain tumors like DMG.
