Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.

Cell metabolism Pub Date : 2024-04-02 Epub Date: 2024-02-19 DOI:10.1016/j.cmet.2024.01.018
ChuanJie Zhang, ZunGuo Du, Yi Gao, Kiat Shenq Lim, WenJie Zhou, Hai Huang, HongChao He, Jun Xiao, DanFeng Xu, QingQuan Li
{"title":"Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.","authors":"ChuanJie Zhang, ZunGuo Du, Yi Gao, Kiat Shenq Lim, WenJie Zhou, Hai Huang, HongChao He, Jun Xiao, DanFeng Xu, QingQuan Li","doi":"10.1016/j.cmet.2024.01.018","DOIUrl":null,"url":null,"abstract":"<p><p>Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cmet.2024.01.018","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/19 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

肿瘤相关周细胞分泌的蛋氨酸支持透明细胞肾癌中的癌症干细胞。
在这里,我们发现了一个由血小板衍生生长因子受体β(PDGFR-β)和G蛋白偶联受体91(GPR91)的表达所定义的血管周细胞亚群,它们在透明细胞肾细胞癌(ccRCC)中作为癌症干细胞(CSCs)的主要蛋氨酸来源,促进了肿瘤发生和酪氨酸激酶抑制剂(TKIs)的耐药性。肿瘤细胞衍生的琥珀酸与包膜细胞上的GPR91结合,激活自噬以产生蛋氨酸。CSCs利用蛋氨酸在含ATPase-family-AAA-domain-containing 2(ATAD2)mRNA中产生稳定的N6-甲基腺苷,由此产生的ATAD2蛋白与SRY-box转录因子9复合物组装成超级增强子,从而决定其在CSCs中具有显著特征的靶基因。用特异性GRP91拮抗剂靶向PDGFR-β+GPR91+周细胞,可降低瘤内蛋氨酸水平、消除CSCs并提高TKIs的敏感性。这些结果揭示了PDGFR-β+GPR91+周细胞为CSCs提供支持性龛位的机制,可用于开发治疗ccRCC的靶点。
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
自引率
0.00%
发文量
0
×
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:481959085
Book学术官方微信