Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-06-17 DOI:10.1038/s41368-024-00310-2
Lixuan Wang, Rongchun Yang, Yue Kong, Jing Zhou, Yingyao Chen, Rui Li, Chuwen Chen, Xinran Tang, Xiaobing Chen, Juan Xia, Xijuan Chen, Bin Cheng, Xianyue Ren
{"title":"Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC","authors":"Lixuan Wang, Rongchun Yang, Yue Kong, Jing Zhou, Yingyao Chen, Rui Li, Chuwen Chen, Xinran Tang, Xiaobing Chen, Juan Xia, Xijuan Chen, Bin Cheng, Xianyue Ren","doi":"10.1038/s41368-024-00310-2","DOIUrl":null,"url":null,"abstract":"<p>Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8<sup>+</sup> T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":10.8000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Oral Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41368-024-00310-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DENTISTRY, ORAL SURGERY & MEDICINE","Score":null,"Total":0}
引用次数: 0

Abstract

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

Abstract Image

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
单细胞和大容量转录组的整合分析揭示了丝氨酸-甘氨酸-一碳代谢的异质性与 HNSCC 的不同预后和治疗脆弱性的关系
代谢异质性在维持不受控制的癌细胞增殖和塑造肿瘤微环境(TME)方面发挥着核心作用,这严重影响了头颈部鳞状细胞癌(HNSCC)患者的临床疗效和治疗反应。这凸显出迫切需要明确代谢脆弱性的内在异质性和生物学作用,以推进精准肿瘤学的发展。利用单细胞RNA测序(scRNA-seq)图谱确定了恶性细胞的代谢异质性,并通过大体转录组进行了验证。筛选出丝氨酸-甘氨酸-一碳(SGOC)代谢是导致HNSCC患者恶性侵袭性和预后不良的原因。通过LASSO-COX回归分析构建的4-SGOC基因预后特征对总生存期和治疗反应有良好的预测作用。低风险组患者的CD8+ T细胞浸润程度更高,接受免疫疗法和化疗后的临床疗效更好。相反,高危患者表现出冷肿瘤的特征,IMPDH1介导的嘌呤生物合成增强,导致对目前疗法的反应不佳。IMPDH1 成为潜在的治疗代谢靶点。用IMPDH抑制剂治疗可有效抑制HNSCC细胞的增殖和转移,并通过引发GTP耗竭核应激诱导体外和体内细胞凋亡。我们的研究结果强调了 HNSCC 的代谢脆弱性,有助于对患者进行准确分层和个体化的精准代谢靶向治疗。
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 去求助
来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
期刊最新文献
Organoids in the oral and maxillofacial region: present and future. Personalized bioceramic grafts for craniomaxillofacial bone regeneration An unexpected role of neurite outgrowth inhibitor A as regulator of tooth enamel formation Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches. CREB3L1 deficiency impairs odontoblastic differentiation and molar dentin deposition partially through the TMEM30B.
×
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