Department of Computer and Information Technology, Purdue University, Indiana, USA.
Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indiana, USA.
Brief Bioinform. 2023 Sep 22;24(6). doi: 10.1093/bib/bbad338.
Spatial cellular authors heterogeneity contributes to differential drug responses in a tumor lesion and potential therapeutic resistance. Recent emerging spatial technologies such as CosMx, MERSCOPE and Xenium delineate the spatial gene expression patterns at the single cell resolution. This provides unprecedented opportunities to identify spatially localized cellular resistance and to optimize the treatment for individual patients. In this work, we present a graph-based domain adaptation model, SpaRx, to reveal the heterogeneity of spatial cellular response to drugs. SpaRx transfers the knowledge from pharmacogenomics profiles to single-cell spatial transcriptomics data, through hybrid learning with dynamic adversarial adaption. Comprehensive benchmarking demonstrates the superior and robust performance of SpaRx at different dropout rates, noise levels and transcriptomics coverage. Further application of SpaRx to the state-of-the-art single-cell spatial transcriptomics data reveals that tumor cells in different locations of a tumor lesion present heterogenous sensitivity or resistance to drugs. Moreover, resistant tumor cells interact with themselves or the surrounding constituents to form an ecosystem for drug resistance. Collectively, SpaRx characterizes the spatial therapeutic variability, unveils the molecular mechanisms underpinning drug resistance and identifies personalized drug targets and effective drug combinations.
空间细胞作者异质性导致肿瘤病变中药物反应的差异和潜在的治疗耐药性。最近出现的空间技术，如 CosMx、MERSCOPE 和 Xenium，可在单细胞分辨率下描绘空间基因表达模式。这为识别空间上局部的细胞耐药性并为个体患者优化治疗提供了前所未有的机会。在这项工作中，我们提出了一种基于图的域自适应模型 SpaRx，以揭示药物对空间细胞反应的异质性。SpaRx 通过混合动态对抗适应的学习，将药理学特征知识传递到单细胞空间转录组学数据中。全面的基准测试表明，SpaRx 在不同的丢包率、噪声水平和转录组覆盖度下具有优越和稳健的性能。SpaRx 进一步应用于最先进的单细胞空间转录组学数据揭示了肿瘤病变中不同位置的肿瘤细胞对药物表现出异质性的敏感性或耐药性。此外，耐药肿瘤细胞与自身或周围成分相互作用，形成耐药的生态系统。总之，SpaRx 描述了空间治疗变异性，揭示了耐药性的分子机制，并确定了个性化的药物靶点和有效的药物组合。
