Background: Brain metastasis occurs in 40–50% of lung cancer patients and is associated with poor prognosis. This study aimed to identify potential exosomal biomarkers for the early detection of brain metastasis in lung cancer using a comprehensive multi-omics approach. Methods: Using a lung cancer mouse model, which develops brain metastasis, we collected serum samples at different stages (control, 6 weeks for lung cancer, and 10 weeks for brain metastasis). We profiled the contents of serum-derived exosomes using small RNA sequencing and LC-MS/MS proteomic analysis, and assessed the clinical relevance of candidate biomarkers using publicly available patient datasets. Results: RNA sequencing identified 11 differentially expressed miRNAs across disease progression, with miR-206-3p showing significant upregulation during brain metastasis. Pathway analysis of miR-206-3p targets revealed enrichment in cancer-related pathways, including Hippo, MAPK, Ras, and PI3K-Akt signaling. Proteomic analysis revealed 77 proteins specifically upregulated in the brain metastasis stage, with vinculin (VCL) emerging as a promising marker. While VCL expression decreased in lung tissues and showed no significant changes in brain tissues, its levels were significantly elevated in serum-derived exosomes during brain metastasis. Clinical database analysis revealed that higher VCL expression correlated with poor patient survival. Conclusions: Our study identified exosomal miR-206-3p and VCL as promising non-invasive biomarkers for brain metastasis in lung cancer using the mouse model. These findings provide new opportunities for early detection and monitoring of brain metastasis, potentially enabling timely therapeutic intervention.
背景：脑转移发生于40%-50%的肺癌患者，且与不良预后相关。本研究旨在通过综合多组学方法，寻找可用于肺癌脑转移早期检测的潜在外泌体生物标志物。方法：利用可发生脑转移的肺癌小鼠模型，我们在不同阶段（对照组、肺癌6周组和脑转移10周组）采集血清样本。通过小RNA测序和LC-MS/MS蛋白质组学分析，我们对血清来源外泌体的内容物进行了分析，并利用公开的患者数据集评估了候选生物标志物的临床相关性。结果：RNA测序鉴定出11种在疾病进展过程中差异表达的miRNA，其中miR-206-3p在脑转移阶段显著上调。对miR-206-3p靶点的通路分析显示，其在癌症相关通路中富集，包括Hippo、MAPK、Ras和PI3K-Akt信号通路。蛋白质组学分析揭示了77种在脑转移阶段特异性上调的蛋白质，其中纽蛋白（VCL）成为一个有前景的标志物。尽管VCL在肺组织中表达下降，在脑组织中未见显著变化，但其在脑转移阶段的血清来源外泌体中水平显著升高。临床数据库分析显示，较高的VCL表达与患者较差的生存率相关。结论：本研究利用小鼠模型，鉴定出外泌体miR-206-3p和VCL作为肺癌脑转移有前景的非侵入性生物标志物。这些发现为脑转移的早期检测和监测提供了新的机会，可能有助于实现及时的治疗干预。
肿瘤(癌症)患者之家