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., Grajal HC; Spanish National Center for Cardiovascular Research, Madrid, Spain., Higgins DMO; Department of Neurological Surgery, University of North Carolina School of Medicine, Chapel Hill, NC, USA., Sperring CP; 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 and Department of Chemistry, Columbia University, New York, NY, USA., Nguyen TTT; Department of Pathology and Cell Biology, 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., 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., Bruce JN; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA., Stockwell BR; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA., Sims PA; Department of System Biology, Columbia University Irving Medical Center, New York, NY, USA., Canoll PD; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 23. Date of Electronic Publication: 2023 Feb 23.
DOI:	10.1101/2023.02.22.529581
Abstrakt:	Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Competing Interests: Declaration of interests: The authors declare no competing interests.
Databáze:	MEDLINE
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