ets1驱动的核仁应激协调OLR1+巨噬细胞串扰维持透明细胞肾细胞癌的免疫抑制微环境

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang
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引用次数: 0

摘要

虽然缺氧驱动的核核应激(NS)已被认为是透明细胞肾细胞癌(ccRCC)中免疫抑制肿瘤微环境的关键调节剂,但其对疾病进展的机制贡献仍不清楚。为了解决这一差距,我们通过整合空间转录组学和ccRCC标本的单细胞RNA测序,系统地绘制了ns相关的分子景观。我们的分析将肿瘤分为两种不同的NS亚型,揭示高NS肿瘤表现出侵袭性临床行为,免疫抑制检查点表达升高,生存率显著降低。在单细胞分辨率下,高ns恶性细胞表现出增强的增殖活性、糖酵解代谢重编程和显著的染色体不稳定性。机制研究表明,缺氧诱导的ETS1激活通过MYC/NPM1/DDX17信号轴协调NS,在临床前模型中直接促进肿瘤增殖和代谢适应。空间多组学进一步揭示了高ns细胞和OLR1+巨噬细胞之间协调的生态位形成,配体-受体谱分析鉴定了EDN1-EDNRA-OLR1轴是这种免疫抑制串扰的中心介质。在同基因小鼠模型中的功能验证证实,ETS1过表达加速肿瘤生长,同时富集具有免疫抑制表型的OLR1+巨噬细胞。临床上,在独立队列中,高OLR1+巨噬细胞浸润与较短的生存期相关。这些发现确立了缺氧- ets1 - NS -巨噬细胞轴是维持ccRCC进展的关键机制,并强调了通过调节NS通路破坏致瘤性免疫生态位的可行靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma

ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma

While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1+ macrophages, with ligand–receptor profiling identifying the EDN1–EDNRA–OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1+ macrophages with immunosuppressive phenotypes. Clinically, high OLR1+ macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia–ETS1–NS–macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.

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来源期刊
Human Mutation
Human Mutation 医学-遗传学
CiteScore
8.40
自引率
5.10%
发文量
190
审稿时长
2 months
期刊介绍: Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.
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