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

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
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
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引用次数: 0

摘要

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。

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

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

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.

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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.
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