Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll
{"title":"在胶质母细胞瘤中,细胞对 GPX4 依赖性铁氧化作用的代谢脆弱性具有特异性。","authors":"Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll","doi":"10.1038/s44318-024-00176-4","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480389/pdf/","citationCount":"0","resultStr":"{\"title\":\"A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.\",\"authors\":\"Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll\",\"doi\":\"10.1038/s44318-024-00176-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
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.
期刊介绍:
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