1. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
- Author
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Banu, Matei A, Dovas, Athanassios, Argenziano, Michael G, Zhao, Wenting, Sperring, Colin P, Cuervo Grajal, Henar, Liu, Zhouzerui, Higgins, Dominique MO, Amini, Misha, Pereira, Brianna, Ye, Ling F, Mahajan, Aayushi, Humala, Nelson, Furnari, Julia L, Upadhyayula, Pavan S, Zandkarimi, Fereshteh, Nguyen, Trang TT, Teasley, Damian, Wu, Peter B, and Hai, Li
- Subjects
BRAIN tumors ,DEVELOPMENTAL programs ,CELL populations ,GLIOMAS ,ENERGY metabolism - Abstract
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. Synopsis: The interdependence of oncogenic drivers, cell proliferation and energy metabolism in glioma resistance remains unclear. This study uncovers a unique, targetable metabolic vulnerability of quiescent astrocyte-like glioma cells otherwise resistant to standard forms of treatment. Activating Notch at early stages of gliomagenesis in a retrovirus-induced mouse model drives tumors with an astrocyte-like phenotype. Astrocyte-like glioma cells show decreased mitochondrial respiration and altered complex I function, but increased lipid peroxidation and ROS production. Astrocyte-like glioma cells are specifically vulnerable to the inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treating acute slices generated from human glioma surgical samples with GPX4 inhibitors selectively depletes the quiescent astrocyte-like tumor cells. Quiescent astrocyte-like glioma cells show abnormal energy metabolism, which renders them sensitive to ferroptosis-inducing drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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