SemanticST通过多语义图学习,实现空间转录组数据的高效聚类与生物学解析。
SemanticST: Spatially Informed Semantic Graph Learning for Clustering, Integration, and Scalable Analysis of Spatial Transcriptomics
- 构建空间、表达和组织域三类语义图,融合注意力机制生成统一表征。
- 在四个平台数据上提升20%的聚类精度,支持50万细胞规模的批量训练。
- 可发现罕见癌变区域和新型细胞状态,适合肿瘤空间异质性研究。
空间转录组技术可在空间分辨率下进行基因表达分析,为组织结构与疾病异质性提供新见解。但现有方法常受限于噪声数据、扩展性差及复杂细胞关系建模不足。我们提出SemanticST,一种基于图神经网络的生物启发深度学习框架,通过构建多语义图捕捉空间邻近性、基因表达相似性与组织域结构,学习解耦嵌入并以注意力机制融合,生成统一且具有生物学意义的表征。采用社区感知最小割损失替代对比学习,增强稀疏数据下的鲁棒性。支持小批量训练,首次实现对大规模数据集(如Xenium,50万细胞)的可扩展分析。在四种平台(Visium、Slide-seq、Stereo-seq、Xenium)及多个动植物组织上基准测试显示,其聚类性能(ARI、NMI)和轨迹保真度较DeepST、GraphST、IRIS平均提升20%。乳腺癌Xenium数据重分析中,揭示了三阳性罕见簇、导管原位癌向浸润性癌过渡区等空间特异性区域,以及具有干样特征的FOXC2肿瘤相关肌上皮细胞,提示非经典上皮-间质转化程序。SemanticST为空间转录组分析提供可扩展、可解释且生物学可信的框架,助力跨组织与疾病研究,推动空间解析组织图谱与精准医疗发展。
原文摘要 · Abstract (English)
Spatial transcriptomics (ST) technologies enable gene expression profiling with spatial resolution, offering unprecedented insights into tissue organization and disease heterogeneity. However, current analysis methods often struggle with noisy data, limited scalability, and inadequate modelling of complex cellular relationships. We present SemanticST, a biologically informed, graph-based deep learning framework that models diverse cellular contexts through multi-semantic graph construction. SemanticST builds multiple context-specific graphs capturing spatial proximity, gene expression similarity, and tissue domain structure, and learns disentangled embeddings for each. These are fused using an attention-inspired strategy to yield a unified, biologically meaningful representation. A community-aware min-cut loss improves robustness over contrastive learning, particularly in sparse ST data. SemanticST supports mini-batch training, making it the first graph neural network scalable to large-scale datasets such as Xenium (500,000 cells). Benchmarking across four platforms (Visium, Slide-seq, Stereo-seq, Xenium) and multiple human and mouse tissues shows consistent 20 percentage gains in ARI, NMI, and trajectory fidelity over DeepST, GraphST, and IRIS. In re-analysis of breast cancer Xenium data, SemanticST revealed rare and clinically significant niches, including triple receptor-positive clusters, spatially distinct DCIS-to-IDC transition zones, and FOXC2 tumour-associated myoepithelial cells, suggesting non-canonical EMT programs with stem-like features. SemanticST thus provides a scalable, interpretable, and biologically grounded framework for spatial transcriptomics analysis, enabling robust discovery across tissue types and diseases, and paving the way for spatially resolved tissue atlases and next-generation precision medicine.
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