揭示胶质母细胞瘤及其肿瘤周围微环境中单细胞水平的新型细胞簇和生物标志物。

Unveiling novel cell clusters and biomarkers in glioblastoma and its peritumoral microenvironment at the single-cell perspective.

机构信息

Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China.

出版信息

J Transl Med. 2024 Jun 8;22(1):551. doi: 10.1186/s12967-024-05313-5.

DOI:10.1186/s12967-024-05313-5

PMID:38851695

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11162569/

Abstract

BACKGROUND

Glioblastoma (GBM) is a highly heterogeneous, recurrent and aggressively invasive primary malignant brain tumor. The heterogeneity of GBM results in poor targeted therapy. Therefore, the aim of this study is to depict the cellular landscape of GBM and its peritumor from a single-cell perspective. Discovering new cell subtypes and biomarkers, and providing a theoretical basis for precision therapy.

METHODS

We collected 8 tissue samples from 4 GBM patients to perform 10 × single-cell transcriptome sequencing. Quality control and filtering of data by Seurat package for clustering. Inferring copy number variations to identify malignant cells via the infercnv package. Functional enrichment analysis was performed by GSVA and clusterProfiler packages. STRING database and Cytoscape software were used to construct protein interaction networks. Inferring transcription factors by pySCENIC. Building cell differentiation trajectories via the monocle package. To infer intercellular communication networks by CellPhoneDB software.

RESULTS

We observed that the tumor microenvironment (TME) varies among different locations and different GBM patients. We identified a proliferative cluster of oligodendrocytes with high expression of mitochondrial genes. We also identified two clusters of myeloid cells, one primarily located in the peritumor exhibiting an M1 phenotype with elevated TNFAIP8L3 expression, and another in the tumor and peritumor showing a proliferative tendency towards an M2 phenotype with increased DTL expression. We identified XIST, KCNH7, SYT1 and DIAPH3 as potential factors associated with the proliferation of malignant cells in GBM.

CONCLUSIONS

These biomarkers and cell clusters we discovered may serve as targets for treatment. Targeted drugs developed against these biomarkers and cell clusters may enhance treatment efficacy, optimize immune therapy strategies, and improve the response rates of GBM patients to immunotherapy. Our findings provide a theoretical basis for the development of individualized treatment and precision medicine for GBM, which may be used to improve the survival of GBM patients.

摘要

背景

胶质母细胞瘤（GBM）是一种高度异质性、复发性和侵袭性强的原发性恶性脑肿瘤。GBM 的异质性导致靶向治疗效果不佳。因此，本研究旨在从单细胞角度描绘 GBM 及其周围肿瘤的细胞景观。发现新的细胞亚型和生物标志物，为精准治疗提供理论依据。

方法

我们收集了 4 名 GBM 患者的 8 个组织样本进行 10×单细胞转录组测序。使用 Seurat 包对数据进行质量控制和过滤，通过 infercnv 包推断拷贝数变异以识别恶性细胞。通过 GSVA 和 clusterProfiler 包进行功能富集分析。使用 STRING 数据库和 Cytoscape 软件构建蛋白质相互作用网络。通过 pySCENIC 推断转录因子。使用 monocle 包构建细胞分化轨迹。使用 CellPhoneDB 软件推断细胞间通讯网络。

结果

我们观察到肿瘤微环境（TME）在不同位置和不同 GBM 患者之间存在差异。我们鉴定出一个具有高表达线粒体基因的少突胶质细胞增殖簇。我们还鉴定出两个髓样细胞簇，一个主要位于肿瘤周围，表现出 M1 表型，TNFAIP8L3 表达升高，另一个位于肿瘤和肿瘤周围，表现出向 M2 表型增殖的趋势，DTL 表达增加。我们鉴定出 XIST、KCNH7、SYT1 和 DIAPH3 作为与 GBM 中恶性细胞增殖相关的潜在因素。