A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
Astrocytic
Ferroptosis
Glioma
Mitochondrial-metabolism
Quiescent
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
received:
23
04
2024
accepted:
01
07
2024
revised:
12
06
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
aheadofprint
Résumé
Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
Identifiants
pubmed: 39192032
doi: 10.1038/s44318-024-00176-4
pii: 10.1038/s44318-024-00176-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS103473
Organisme : HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS103473
Organisme : HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS103473
Organisme : HHS | National Institutes of Health (NIH)
ID : R35CA209896
Organisme : HHS | National Institutes of Health (NIH)
ID : R01HL112626
Organisme : HHS | NIH | National Cancer Institute (NCI)
ID : P30CA013696
Informations de copyright
© 2024. The Author(s).
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