A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles.

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-02-24 eCollection Date: 2025-01-01 DOI:10.7150/thno.103722
Jingyi Wang, Liu Liu, Xinyu Gao, Xiyu Liu, Yitian Dai, Zijun Mao, Shengzhe Huang, Junjian Li, Dongliang Wang, Yu Qi, Yingwen Han, Yunjing Xu, Corrine Ying Xuan Chua, Alessandro Grattoni, Wenhui Xie, Hao Yang, Gang Huang
{"title":"A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles.","authors":"Jingyi Wang, Liu Liu, Xinyu Gao, Xiyu Liu, Yitian Dai, Zijun Mao, Shengzhe Huang, Junjian Li, Dongliang Wang, Yu Qi, Yingwen Han, Yunjing Xu, Corrine Ying Xuan Chua, Alessandro Grattoni, Wenhui Xie, Hao Yang, Gang Huang","doi":"10.7150/thno.103722","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. <b>Methods:</b> <i>In vitro</i> and <i>in vivo</i> experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. <b>Results</b>: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. <b>Conclusion:</b> This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 8","pages":"3439-3461"},"PeriodicalIF":12.4000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905138/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.103722","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. Methods: In vitro and in vivo experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. Results: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. Conclusion: This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.

通过磷酸化PKM2-负载的细胞外小泡实现非小细胞肺癌干性传播和化疗耐药性的新途径
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
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
×
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