Roza H A Masalmeh, John C Dawson, Virginia Alvarez Garcia, Morwenna T Muir, Roderick N Carter, Giles Hardingham, Cameron Davies, Rosina Graham, Alex von Kriegsheim, Jair Marques, Chinmayi Pednekar, Steven M Pollard, Neil O Carragher, Valerie G Brunton, Margaret C Frame
{"title":"FAK通过调节糖酵解和谷氨酰胺氧化来调节胶质母细胞瘤干细胞的能量。","authors":"Roza H A Masalmeh, John C Dawson, Virginia Alvarez Garcia, Morwenna T Muir, Roderick N Carter, Giles Hardingham, Cameron Davies, Rosina Graham, Alex von Kriegsheim, Jair Marques, Chinmayi Pednekar, Steven M Pollard, Neil O Carragher, Valerie G Brunton, Margaret C Frame","doi":"10.1242/dmm.052634","DOIUrl":null,"url":null,"abstract":"<p><p>Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still un known. We show that the canonical cell-ECM adhesion protein FAK, and specifically its kinase activity, is driving cellular energetics. Using a stem cell model of glioblastoma, we show that FAK gene deletion simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at S235 and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19). This can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK-ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function, and malignant behaviour.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.\",\"authors\":\"Roza H A Masalmeh, John C Dawson, Virginia Alvarez Garcia, Morwenna T Muir, Roderick N Carter, Giles Hardingham, Cameron Davies, Rosina Graham, Alex von Kriegsheim, Jair Marques, Chinmayi Pednekar, Steven M Pollard, Neil O Carragher, Valerie G Brunton, Margaret C Frame\",\"doi\":\"10.1242/dmm.052634\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still un known. We show that the canonical cell-ECM adhesion protein FAK, and specifically its kinase activity, is driving cellular energetics. Using a stem cell model of glioblastoma, we show that FAK gene deletion simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at S235 and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19). This can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK-ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function, and malignant behaviour.</p>\",\"PeriodicalId\":11144,\"journal\":{\"name\":\"Disease Models & Mechanisms\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-09-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Disease Models & Mechanisms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1242/dmm.052634\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.052634","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.
Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still un known. We show that the canonical cell-ECM adhesion protein FAK, and specifically its kinase activity, is driving cellular energetics. Using a stem cell model of glioblastoma, we show that FAK gene deletion simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at S235 and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19). This can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK-ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function, and malignant behaviour.
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.