通过小鼠呼出气体冷凝物和呼出细胞外囊泡的 microRNA 表达谱分析无创检测人体正位肺肿瘤

M. Mitchell, I. Ben-Dov, Christina Liu, Tao Wang, Rachel B. Hazan, Thomas L. Bauer, Johannes Zakrzewski, Kathryn Donnelly, Kar Chow, Junfeng Ma, Olivier Loudig
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摘要

目的:肺部是第二大最常见的转移扩散部位。早期检测是提高生存率的关键。由于肺部与外部环境相通,收集呼出的冷凝液(EBC)可获得生物材料,包括源自肺部的呼出 miRNA。方法:在这项原理验证研究中,我们利用高度转移性的 MDA-MB-231 亚系 3475 乳腺癌细胞系(LM-3475)建立了一个正位肺肿瘤小鼠模型,并研究了通过分析呼出的 miRNAs 来无创检测肺肿瘤的方法。我们最初对从无拘束动物身上收集的冷凝物进行了 miRNA NGS 和 qPCR 验证分析,发现肺肿瘤小鼠和对照小鼠的冷凝物之间存在显著的 miRNA 表达差异。为了集中纯化 EBC 并评估这些不同表达 miRNA 的来源,我们开发了一套系统,直接从小鼠的口鼻中收集 EBC。结果通过纳米粒子分布分析、TEM 和 ONi 超分辨率纳米成像,我们确定在继发性肺肿瘤的发展过程中,小鼠 EBC 中能检测到越来越多的人类肿瘤 EV。我们利用可定制的 EV-CATCHER 检测方法,从小鼠 EBC 中纯化出了人类肿瘤 EV,并证明了大部分不同表达的呼出 miRNA 来自肺肿瘤,这些 miRNA 可在尾静脉注射转移细胞后 1 到 2 周内通过 qPCR 检测到。结论该研究首次证明了小鼠呼出的肺肿瘤 EVs 可作为检测肺肿瘤的非侵入性生物标记物。
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Non-invasive detection of orthotopic human lung tumors by microRNA expression profiling of mouse exhaled breath condensates and exhaled extracellular vesicles
Aim: The lung is the second most frequent site of metastatic dissemination. Early detection is key to improving survival. Given that the lung interfaces with the external environment, the collection of exhaled breath condensate (EBC) provides the opportunity to obtain biological material including exhaled miRNAs that originate from the lung. Methods: In this proof-of-principal study, we used the highly metastatic MDA-MB-231 subline 3475 breast cancer cell line (LM-3475) to establish an orthotopic lung tumor-bearing mouse model and investigate non-invasive detection of lung tumors by analysis of exhaled miRNAs. We initially conducted miRNA NGS and qPCR validation analyses on condensates collected from unrestrained animals and identified significant miRNA expression differences between the condensates of lung tumor-bearing and control mice. To focus our purification of EBC and evaluate the origin of these differentially expressed miRNAs, we developed a system to collect EBC directly from the nose and mouth of our mice. Results: Using nanoparticle distribution analyses, TEM, and ONi super-resolution nanoimaging, we determined that human tumor EVs could be increasingly detected in mouse EBC during the progression of secondary lung tumors. Using our customizable EV-CATCHER assay, we purified human tumor EVs from mouse EBC and demonstrated that the bulk of differentially expressed exhaled miRNAs originate from lung tumors, which could be detected by qPCR within 1 to 2 weeks after tail vein injection of the metastatic cells. Conclusion: This study is the first of its kind and demonstrates that lung tumor EVs are exhaled in mice and provide non-invasive biomarkers for detection of lung tumors.
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