单核RNA测序揭示了全脑基因网络对小细胞肺癌反应的关键变化
Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing.
摘要(中文译文)
小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌恶性肿瘤，神经活动被认为参与其肿瘤进展。然而，原发性SCLC是否对大脑产生系统性影响仍不确定。我们利用驱动型SCLC小鼠模型，进行了全脑单核RNA测序（n = 48,686个细胞核），并结合肺肿瘤和血浆的转录组学与代谢组学分析，在公开的SCLC队列中验证了我们的发现。此外，还应用了氟马西尼对GABA受体的药理学抑制。我们观察到荷瘤小鼠全脑存在广泛的、细胞类型分辨的转录改变。基底节细胞和GABA能抑制性神经元中表达广泛增加。同时，少突胶质前体细胞表现出成熟受损，伴随髓鞘形成相关基因（、、）的协同下调。代谢组学分析显示，与假处理对照组相比，荷瘤小鼠肺肿瘤中谷氨酸和GABA水平显著升高。临床测量表明，SCLC患者血浆中谷氨酸和GABA明显升高，提示这些神经递质与肿瘤进展相关的系统性升高。此外，氟马西尼对GABA受体的药理学抑制显著抑制了肿瘤生长。原发性SCLC与细胞类型特异性的大脑转录重塑及循环谷氨酸升高相关，为肺-脑代谢轴提供了描述性证据。然而，该轴内的直接因果联系仍有待未来的干预性研究加以确立。
Abstract
Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy in which neural activity is implicated in tumor progression. Nevertheless, whether primary SCLC elicits systemic effects on the brain remains uncertain. Using an -driven SCLC mouse model, we performed whole-brain single-nucleus RNA sequencing (n = 48,686 nuclei) integrated with transcriptomic and metabolomic analyses of lung tumors and plasma, validating our findings across public SCLC cohorts. Pharmacological inhibition of GABA receptors with flumazenil was also applied . We observed widespread, cell-type-resolved transcriptional alterations across the brain in tumor-bearing mice. expression broadly increased in basal ganglia cells and GABAergic inhibitory neurons. Concurrently, oligodendrocyte precursor cells exhibited impaired maturation, accompanied by coordinated downregulation of myelination-related genes (, , ). Metabolomic analyses demonstrated significantly higher levels of glutamate and GABA in lung tumors from tumor-bearing mice relative to sham-treated controls. Clinical measurements indicated that glutamate and GABA were markedly increased in SCLC patient plasma, suggesting a systemic elevation of these neurotransmitters associated with tumor progression. Furthermore, pharmacological inhibition of GABA receptors with flumazenil significantly suppressed tumor growth . Primary SCLC is associated with cell-type-specific brain transcriptional remodeling and elevated circulating glutamate, providing descriptive evidence for a lung-brain metabolic axis. However, direct causal links within this axis remain to be established through future interventional studies.
如何引用
AMA
Jingwei Duan, Qi Fu, Yongkun Huo, Caifang Wang, Yuke Shen, Mingtian Zhong, et al. Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1860628.
APA
Jingwei Duan, Qi Fu, Yongkun Huo, Caifang Wang, Yuke Shen, Mingtian Zhong, et al (2026). Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1860628
GB/T 7714
Jingwei Duan, Qi Fu, Yongkun Huo, Caifang Wang, Yuke Shen, Mingtian Zhong, et al. Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1860628.
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