FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
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 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}
引用次数: 0

Abstract

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.

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。
糖酵解和TCA循环在癌细胞中被重新编程,以满足生物能量和生物合成的需求,包括与细胞外基质(ECM)的结合。然而,ECM参与重编程核心能量代谢的机制尚不清楚。我们表明典型细胞- ecm粘附蛋白FAK,特别是它的激酶活性,正在驱动细胞能量学。利用胶质母细胞瘤干细胞模型,我们发现FAK基因缺失同时抑制糖酵解和谷氨酰胺氧化,增加线粒体断裂,提高线粒体蛋白MTFR1L在S235位点的磷酸化,并触发间质向上皮的转变。磷酸化肌球蛋白轻链(p-MLC S19)显示,这些代谢和结构变化是通过肌动蛋白收缩性的改变引起的。这可以通过rho激酶(ROCK)抑制剂逆转,揭示线粒体动力学和谷氨酰胺氧化的机械转导途径控制。fak依赖性代谢编程与体内细胞迁移、侵袭能力和肿瘤生长的调节有关。我们的工作描述了一个以前未被识别的FAK-ROCK轴,它将机械线索与能量代谢的重新连接结合起来,将细胞形状、线粒体功能和恶性行为联系起来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信