A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Autor:	Banu MA; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Dovas A; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Argenziano MG; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Zhao W; Department of System Biology, Columbia University Irving Medical Center, New York, NY, USA., Sperring CP; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Cuervo Grajal H; Spanish National Center for Cardiovascular Research, Madrid, Spain., Liu Z; Department of System Biology, Columbia University Irving Medical Center, New York, NY, USA., Higgins DM; Department of Neurological Surgery, University of North Carolina School of Medicine, Chapel Hill, NC, USA., Amini M; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Pereira B; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Ye LF; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Mahajan A; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Humala N; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Furnari JL; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Upadhyayula PS; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Zandkarimi F; Department of Biological Sciences, Department of Chemistry and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA., Nguyen TT; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Teasley D; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Wu PB; Department of Neurological Surgery, UCLA Geffen School of Medicine, Los Angeles, CA, USA., Hai L; Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA., Karan C; Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA., Dowdy T; NCI Neuro-oncology Branch, Bethesda, MD, USA., Razavilar A; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Siegelin MD; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Kitajewski J; University of Illinois Cancer Center, Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, USA., Larion M; NCI Neuro-oncology Branch, Bethesda, MD, USA., Bruce JN; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Stockwell BR; Department of Biological Sciences, Department of Chemistry and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA., Sims PA; Department of System Biology, Columbia University Irving Medical Center, New York, NY, USA. pas2182@cumc.columbia.edu., Canoll P; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA. pc561@cumc.columbia.edu.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. pc561@cumc.columbia.edu.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Oct; Vol. 43 (20), pp. 4492-4521. Date of Electronic Publication: 2024 Aug 27.
DOI:	10.1038/s44318-024-00176-4
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu