Department of Neurosurgery, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Front Immunol. 2023 Aug 31;14:1263329. doi: 10.3389/fimmu.2023.1263329. eCollection 2023.
Glioblastoma (GBM) is a malignant primary brain tumor. This study focused on exploring the exosome-related features of glioblastoma to better understand its cellular composition and molecular characteristics.
Single-cell RNA sequencing (scRNA-seq) and spatial transcriptome RNA sequencing (stRNA-seq) were used to analyze the heterogeneity of glioblastomas. After data integration, cell clustering, and annotation, five algorithms were used to calculate scores for exosome-related genes(ERGs). Cell trajectory analysis and intercellular communication analysis were performed to explore exosome-related communication patterns. Spatial transcriptome sequencing data were analyzed to validate the findings. To further utilize exosome-related features to aid in clinical decision-making, a prognostic model was constructed using GBM's bulk RNA-seq.
Different cell subpopulations were observed in GBM, with Monocytes/macrophages and malignant cells in tumor samples showing higher exosome-related scores. After identifying differentially expressed ERGs in malignant cells, pseudotime analysis revealed the cellular status of malignant cells during development. Intercellular communication analysis highlighted signaling pathways and ligand-receptor interactions. Spatial transcriptome sequencing confirmed the high expression of exosome-related gene features in the tumor core region. A prognostic model based on six ERGs was shown to be predictive of overall survival and immunotherapy outcome in GBM patients. Finally, based on the results of scRNA-seq and prognostic modeling as well as a series of cell function experiments, BARD1 was identified as a novel target for the treatment of GBM.
This study provides a comprehensive understanding of the exosome-related features of GBM in both scRNA-seq and stRNA-seq, with malignant cells with higher exosome-related scores exhibiting stronger communication with Monocytes/macrophages. In terms of spatial data, highly scored malignant cells were also concentrated in the tumor core region. In bulk RNA-seq, patients with a high exosome-related index exhibited an immunosuppressive microenvironment, which was accompanied by a worse prognosis as well as immunotherapy outcomes. Prognostic models constructed using ERGs are expected to be independent prognostic indicators for GBM patients, with potential implications for personalized treatment strategies for GBM. Knockdown of BARD1 in GBM cell lines reduces the invasive and value-added capacity of tumor cells, and thus BARD1-positively expressing malignant cells are a risk factor for GBM patients.
胶质母细胞瘤（GBM）是一种恶性原发性脑肿瘤。本研究旨在探索胶质母细胞瘤的外泌体相关特征，以更好地了解其细胞组成和分子特征。
采用单细胞 RNA 测序（scRNA-seq）和空间转录组 RNA 测序（stRNA-seq）分析胶质母细胞瘤的异质性。在数据整合、细胞聚类和注释后，使用五种算法计算外泌体相关基因（ERGs）的分数。进行细胞轨迹分析和细胞间通讯分析，以探索外泌体相关的通讯模式。分析空间转录组测序数据以验证发现。为了进一步利用外泌体相关特征辅助临床决策，使用 GBM 的 bulk RNA-seq 构建了预后模型。
在 GBM 中观察到不同的细胞亚群，肿瘤样本中的单核细胞/巨噬细胞和恶性细胞表现出更高的外泌体相关评分。在鉴定恶性细胞中差异表达的 ERGs 后，伪时间分析揭示了恶性细胞在发育过程中的细胞状态。细胞间通讯分析突出了信号通路和配体-受体相互作用。空间转录组测序证实了肿瘤核心区域高表达外泌体相关基因特征。基于六个 ERGs 的预后模型显示，可预测 GBM 患者的总生存和免疫治疗结局。最后，基于 scRNA-seq 和预后建模以及一系列细胞功能实验的结果，鉴定出 BARD1 是 GBM 治疗的新靶点。
本研究在 scRNA-seq 和 stRNA-seq 中全面了解 GBM 的外泌体相关特征，具有更高外泌体相关评分的恶性细胞与单核细胞/巨噬细胞之间表现出更强的通讯。在空间数据方面，评分较高的恶性细胞也集中在肿瘤核心区域。在 bulk RNA-seq 中，外泌体相关指数较高的患者表现出免疫抑制微环境，预后较差，免疫治疗效果也较差。使用 ERGs 构建的预后模型有望成为 GBM 患者的独立预后指标，为 GBM 患者的个性化治疗策略提供了潜在依据。在 GBM 细胞系中敲低 BARD1 可降低肿瘤细胞的侵袭性和增值能力，因此 BARD1 阳性表达的恶性细胞是 GBM 患者的一个危险因素。
