Zhou Qirui, Li Chaowen, Chen Chao, Gu Songqing, Sun Weijun, Zhang Zongmeng, Cai Yishan, Huang Yonghui, Liu Hongtao, Yang Chao, Chen Xin
School of Automation, Guangdong University of Technology, No. 100 Waihuan Xi Road, Guangzhou Higher Education Mega Center, Panyu District, Guangzhou 510006, China.
Intelligent Systems and Optimization Integration, School of Automation, Guangdong University of Technology, No. 100 Waihuan Xi Road, Guangzhou Higher Education Mega Center, Panyu District, Guangzhou 510006, China.
Brief Bioinform. 2025 Jul 2;26(4). doi: 10.1093/bib/bbaf365.
Spatial transcriptomics (ST) comprehensively measure the gene expression profiles while preserving the spatial information. Accumulated computational frameworks have been proposed to identify spatial domains, one of the fundamental tasks of ST data analysis, to understand the tissue architecture. However, current methods often overlook pathway-level functional context and struggle with data sparsity. Therefore, we develop Path-MGCN, a multi-view graph convolutional network (GCN) with attention mechanism, which integrates pathway information. We first calculate spot-level pathway activity scores via gene set variation analysis from gene expression and construct distinct adjacency graphs representing spatial and functional proximity. A multi-view GCN learns spatial, pathway, and shared embeddings adaptively fused by attention and followed by a Zero-inflated negative binomial decoder to retain the original transcriptome information. Comprehensive evaluations across diverse datasets (human dorsolateral prefrontal cortex, breast cancer and mouse brain) at various resolution demonstrate Path-MGCN's superior accuracy and robustness, significantly outperforming state-of-the-art methods and maintaining high performance across different pathway databases (Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, Reactome). Crucially, Path-MGCN enhances biological interpretability, enabling the identification of Tertiary lymphoid structure-like regions and spatially resolved metabolic heterogeneity (hypoxia, glycolysis, AMP-activated protein kinase signaling) linked to tumor progression stages in human breast cancer. By effectively integrating functional context, Path-MGCN advances ST analysis, providing an accurate and interpretable framework to dissect tissue heterogeneity and enables detailed spatial mapping of molecular pathways that highlights potential targeted therapeutic strategies crucial for developing safe and effective synergistic anti-tumor therapies.
空间转录组学(ST)在保留空间信息的同时全面测量基因表达谱。已经提出了多种计算框架来识别空间域,这是ST数据分析的基本任务之一,以了解组织结构。然而,当前的方法常常忽略通路水平的功能背景,并且难以处理数据稀疏性问题。因此,我们开发了Path-MGCN,一种具有注意力机制的多视图图卷积网络(GCN),它整合了通路信息。我们首先通过基因集变异分析从基因表达中计算斑点水平的通路活性得分,并构建代表空间和功能邻近性的不同邻接图。一个多视图GCN学习通过注意力自适应融合的空间、通路和共享嵌入,随后是一个零膨胀负二项式解码器以保留原始转录组信息。在不同分辨率下对各种数据集(人类背外侧前额叶皮层、乳腺癌和小鼠脑)进行的综合评估表明,Path-MGCN具有卓越的准确性和鲁棒性,显著优于现有方法,并且在不同的通路数据库(京都基因与基因组百科全书、基因本体论、Reactome)中均保持高性能。至关重要的是,Path-MGCN增强了生物学可解释性,能够识别三级淋巴结构样区域以及与人类乳腺癌肿瘤进展阶段相关的空间分辨代谢异质性(缺氧、糖酵解、AMP激活的蛋白激酶信号传导)。通过有效整合功能背景,Path-MGCN推动了ST分析,提供了一个准确且可解释的框架来剖析组织异质性,并能够对分子通路进行详细的空间映射,突出了对于开发安全有效的协同抗肿瘤疗法至关重要的潜在靶向治疗策略。
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