蛋白质代谢组学和患者肿瘤切片实验表明,氨基酸是纤维乳头状癌线粒体重新配线的核心。

IF 11.7 1区 医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-08-28 DOI:10.1016/j.xcrm.2024.101699
Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy
{"title":"蛋白质代谢组学和患者肿瘤切片实验表明,氨基酸是纤维乳头状癌线粒体重新配线的核心。","authors":"Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy","doi":"10.1016/j.xcrm.2024.101699","DOIUrl":null,"url":null,"abstract":"<p><p>Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7000,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528240/pdf/","citationCount":"0","resultStr":"{\"title\":\"Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.\",\"authors\":\"Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy\",\"doi\":\"10.1016/j.xcrm.2024.101699\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.</p>\",\"PeriodicalId\":9822,\"journal\":{\"name\":\"Cell Reports Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.7000,\"publicationDate\":\"2024-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528240/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Reports Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xcrm.2024.101699\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2024.101699","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

纤维母细胞瘤(FLC)是一种罕见、致命、早发的肝癌,亟需新疗法。FLC的主要驱动因素是融合肿瘤蛋白DNAJ-PKAc,而针对该蛋白的治疗仍具有挑战性。因此,扩大对 FLC 分子图谱的了解以确定可用于治疗的途径/靶点至关重要。在这里,我们对 FLC 进行了最全面的蛋白质代谢组学综合分析。我们还对患者的 FLC 肿瘤组织切片进行了营养操纵、呼吸测定分析以及关键功能缺失测定。我们提出了一个 FLC 细胞能量学模型,指出脯氨酸合成代谢是由鸟氨酸氨基转移酶活性过高和鸟氨酸转氨酶活性过低介导的,而丝氨酸和谷氨酰胺分解代谢为这一过程提供了燃料。我们强调了 FLC 对电压依赖性阴离子通道(VDAC)的潜在依赖性,VDAC 是线粒体阴离子(包括丙酮酸)的看门人。我们在模型中提出的 FLC 代谢重新布线(重点是线粒体)可被用于寻找治疗漏洞。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
期刊最新文献
Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma. Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay. Bifidobacteria with indole-3-lactic acid-producing capacity exhibit psychobiotic potential via reducing neuroinflammation. Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma. Effect of remote ischemic preconditioning on cerebral circulation time in severe carotid artery stenosis: Results from the RIC-CCT trial.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1