• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

皮肤表皮中的代谢重编程驱动对致癌突变的耐受性。

Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.

作者信息

Hemalatha Anupama, Li Zongyu, Gonzalez David G, Matte-Martone Catherine, Tai Karen, Lathrop Elizabeth, Gil Daniel, Ganesan Smirthy, Gonzalez Lauren E, Skala Melissa, Perry Rachel J, Greco Valentina

机构信息

Department of Genetics, Yale School of Medicine, New Haven, CT, USA.

Departments of Cellular & Molecular Physiology and Internal Medicine (Endocrinology), Yale School of Medicine, New Haven, CT, USA.

出版信息

Nat Cell Biol. 2025 Feb;27(2):218-231. doi: 10.1038/s41556-024-01574-w. Epub 2025 Jan 6.

DOI:10.1038/s41556-024-01574-w
PMID:39762578
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11821535/
Abstract

Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, Hras cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and Hras mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the Hrasmodel. Using C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and Hras mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.

摘要

皮肤上皮干细胞可纠正致癌突变诱导的异常。癌基因引发不同的上皮耐受策略；野生型细胞胜过β-连环蛋白功能获得性（βcatGOF）细胞，而Hras细胞胜过野生型细胞。在此，我们探究野生型干细胞与突变细胞相互作用并驱动不同细胞竞争结果时代谢状态如何变化。通过在同一小鼠中随时间以单细胞分辨率追踪内源性氧化还原比率（NAD(P)H/FAD），我们发现βcatGOF和Hras突变在与野生型表皮干细胞相互作用时，会导致氧化还原比率迅速下降，表明细胞氧化还原状态更趋于氧化。然而，βcatGOF中产生的氧化还原差异会随时间持续存在，而在Hras模型中则会迅速消失。使用液相色谱-串联质谱法，我们发现βcatGOF和Hras突变表皮通过氧化三羧酸循环增加了葡萄糖的相对贡献。用细胞溶质氧化还原调节剂二甲双胍处理可抑制下游突变表型，并逆转两种突变模型的细胞竞争结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/19c102449d9b/41556_2024_1574_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/f2d127597121/41556_2024_1574_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/a154e90a4838/41556_2024_1574_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/1940b1dec969/41556_2024_1574_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/cc86bdfd3c5d/41556_2024_1574_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/5de4d2485eb2/41556_2024_1574_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/62967a1613c0/41556_2024_1574_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4a85f7aa1a05/41556_2024_1574_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4a8ac3aee221/41556_2024_1574_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/69d68a32f272/41556_2024_1574_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/d36164478036/41556_2024_1574_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/7211460052e1/41556_2024_1574_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/0c5badf53971/41556_2024_1574_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4494a7c80cb4/41556_2024_1574_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/cd7b83f1e549/41556_2024_1574_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/41b24cd98897/41556_2024_1574_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/104f47a77669/41556_2024_1574_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/19c102449d9b/41556_2024_1574_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/f2d127597121/41556_2024_1574_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/a154e90a4838/41556_2024_1574_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/1940b1dec969/41556_2024_1574_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/cc86bdfd3c5d/41556_2024_1574_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/5de4d2485eb2/41556_2024_1574_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/62967a1613c0/41556_2024_1574_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4a85f7aa1a05/41556_2024_1574_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4a8ac3aee221/41556_2024_1574_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/69d68a32f272/41556_2024_1574_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/d36164478036/41556_2024_1574_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/7211460052e1/41556_2024_1574_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/0c5badf53971/41556_2024_1574_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/4494a7c80cb4/41556_2024_1574_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/cd7b83f1e549/41556_2024_1574_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/41b24cd98897/41556_2024_1574_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/104f47a77669/41556_2024_1574_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6bc/11821535/19c102449d9b/41556_2024_1574_Fig17_ESM.jpg

相似文献

1
Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.皮肤表皮中的代谢重编程驱动对致癌突变的耐受性。
Nat Cell Biol. 2025 Feb;27(2):218-231. doi: 10.1038/s41556-024-01574-w. Epub 2025 Jan 6.
2
RNAi screens in mice identify physiological regulators of oncogenic growth.RNAi 筛选在小鼠中鉴定出致癌生长的生理调节剂。
Nature. 2013 Sep 12;501(7466):185-90. doi: 10.1038/nature12464. Epub 2013 Aug 14.
3
Reduced HRAS G12V-Driven Tumorigenesis of Cell Lines Expressing KRAS C118S.表达KRAS C118S的细胞系中HRAS G12V驱动的肿瘤发生减少。
PLoS One. 2015 Apr 22;10(4):e0123918. doi: 10.1371/journal.pone.0123918. eCollection 2015.
4
Correction of aberrant growth preserves tissue homeostasis.纠正异常生长可维持组织内稳态。
Nature. 2017 Aug 17;548(7667):334-337. doi: 10.1038/nature23304. Epub 2017 Aug 2.
5
Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice.突变型 Hras(G12V)和 Kras(G12D)在转基因小鼠的肝细胞生长和转化频率上有重叠但不完全相同的作用。
Liver Int. 2012 Apr;32(4):582-91. doi: 10.1111/j.1478-3231.2011.02732.x. Epub 2012 Jan 3.
6
Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis.致癌性 HRAS 突变小鼠对高脂肪饮食诱导的肥胖具有抗性，并表现出肝内能量稳态受损。
EBioMedicine. 2018 Jan;27:138-150. doi: 10.1016/j.ebiom.2017.11.029. Epub 2017 Dec 6.
7
Mutant Nrf2 enhances the promotion and progression of a subset of oncogenic Ras keratinocytes and skin tumors.突变型 Nrf2 增强了一组致癌 Ras 角质形成细胞和皮肤肿瘤的促进和进展。
Redox Biol. 2024 Sep;75:103261. doi: 10.1016/j.redox.2024.103261. Epub 2024 Jun 28.
8
Costello syndrome model mice with a Hras mutation are susceptible to develop house dust mite-induced atopic dermatitis.Hras 突变型 Costello 综合征模型小鼠易患屋尘螨诱导的特应性皮炎。
Cell Death Dis. 2020 Aug 13;11(8):617. doi: 10.1038/s41419-020-02845-8.
9
Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis.野生型和突变型 Ras 基因在肺和皮肤肿瘤发生中的相互作用。
Oncogene. 2013 Aug 22;32(34):4028-33. doi: 10.1038/onc.2012.404. Epub 2012 Sep 3.
10
Exploiting Mouse Models to Study Ras-Induced Cutaneous Squamous Cell Carcinoma.利用小鼠模型研究Ras诱导的皮肤鳞状细胞癌。
J Invest Dermatol. 2016 Aug;136(8):1543-1548. doi: 10.1016/j.jid.2016.03.017. Epub 2016 May 7.

引用本文的文献

1
Bioactive Potential of Flower Extracts: Antidiabetic, Anti-Skin Aging, Cytotoxic, and Dihydroorotase-Inhibitory Activities.花提取物的生物活性潜力：抗糖尿病、抗皮肤衰老、细胞毒性及二氢乳清酸酶抑制活性
Plants (Basel). 2025 Aug 19;14(16):2579. doi: 10.3390/plants14162579.

本文引用的文献

1
C-Stable isotope resolved metabolomics uncovers dynamic biochemical landscape of gut microbiome-host organ communications in mice.C-稳定同位素分辨代谢组学揭示了小鼠肠道微生物组-宿主器官通讯的动态生化景观。
Microbiome. 2024 May 15;12(1):90. doi: 10.1186/s40168-024-01808-x.
2
Label-Free Optical Metabolic Imaging in Cells and Tissues.无标记光学代谢成像在细胞和组织中的应用。
Annu Rev Biomed Eng. 2023 Jun 8;25:413-443. doi: 10.1146/annurev-bioeng-071516-044730. Epub 2023 Apr 27.
3
Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer.
逐渐分化与细胞周期退出脱耦产生表皮干细胞层的异质性。
Nat Cell Biol. 2022 Dec;24(12):1692-1700. doi: 10.1038/s41556-022-01021-8. Epub 2022 Nov 10.
4
Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data.使用 MetaboAnalyst 5.0 进行 LC-HRMS 光谱处理、多组学整合和全局代谢组学数据的协变量调整。
Nat Protoc. 2022 Aug;17(8):1735-1761. doi: 10.1038/s41596-022-00710-w. Epub 2022 Jun 17.
5
In vivo fluorescence lifetime imaging of macrophage intracellular metabolism during wound responses in zebrafish.斑马鱼伤口反应中巨噬细胞内代谢的体内荧光寿命成像。
Elife. 2022 Feb 24;11:e66080. doi: 10.7554/eLife.66080.
6
Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications.线粒体作为二甲双胍的重要靶点：作用机制、毒性和副作用以及新的治疗应用。
Pharmacol Res. 2022 Mar;177:106114. doi: 10.1016/j.phrs.2022.106114. Epub 2022 Feb 3.
7
Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development.细胞竞争在早期小鼠发育过程中充当了一种净化选择，以消除具有线粒体缺陷的细胞。
Nat Metab. 2021 Aug;3(8):1091-1108. doi: 10.1038/s42255-021-00422-7. Epub 2021 Jul 12.
8
Tissue Imaging and Quantification Relying on Endogenous Contrast.基于内源性对比的组织成像与定量。
Adv Exp Med Biol. 2021;3233:257-288. doi: 10.1007/978-981-15-7627-0_12.
9
Cell competition: A historical perspective.细胞竞争：历史透视。
Dev Biol. 2021 Aug;476:33-40. doi: 10.1016/j.ydbio.2021.02.012. Epub 2021 Mar 26.
10
Metabolic regulation of cell competition.细胞竞争的代谢调控。
Dev Biol. 2021 Jul;475:30-36. doi: 10.1016/j.ydbio.2021.02.011. Epub 2021 Feb 27.