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利用 SCAD 从批量 RNA-Seq 中实现单细胞药物反应注释。

Enabling Single-Cell Drug Response Annotations from Bulk RNA-Seq Using SCAD.

机构信息

Department of Computer Science, City University of Hong Kong, Kowloon, Hong Kong.

The Laboratory of Data Discovery for Health (D²4H), Hong Kong Science Park, New Territories, Hong Kong.

出版信息

Adv Sci (Weinh). 2023 Apr;10(11):e2204113. doi: 10.1002/advs.202204113. Epub 2023 Feb 10.

Abstract

The single-cell RNA sequencing (scRNA-seq) quantifies the gene expression of individual cells, while the bulk RNA sequencing (bulk RNA-seq) characterizes the mixed transcriptome of cells. The inference of drug sensitivities for individual cells can provide new insights to understand the mechanism of anti-cancer response heterogeneity and drug resistance at the cellular resolution. However, pharmacogenomic information related to their corresponding scRNA-Seq is often limited. Therefore, a transfer learning model is proposed to infer the drug sensitivities at single-cell level. This framework learns bulk transcriptome profiles and pharmacogenomics information from population cell lines in a large public dataset and transfers the knowledge to infer drug efficacy of individual cells. The results suggest that it is suitable to learn knowledge from pre-clinical cell lines to infer pre-existing cell subpopulations with different drug sensitivities prior to drug exposure. In addition, the model offers a new perspective on drug combinations. It is observed that drug-resistant subpopulation can be sensitive to other drugs (e.g., a subset of JHU006 is Vorinostat-resistant while Gefitinib-sensitive); such finding corroborates the previously reported drug combination (Gefitinib + Vorinostat) strategy in several cancer types. The identified drug sensitivity biomarkers reveal insights into the tumor heterogeneity and treatment at cellular resolution.

摘要

单细胞 RNA 测序 (scRNA-seq) 定量测量单个细胞的基因表达,而批量 RNA 测序 (bulk RNA-seq) 则描述细胞混合转录组的特征。推断单个细胞的药物敏感性可以提供新的见解,以了解抗癌反应异质性和细胞水平耐药性的机制。然而,与其对应的 scRNA-Seq 相关的药物基因组学信息通常是有限的。因此,提出了一种转移学习模型来推断单细胞水平的药物敏感性。该框架从大型公共数据集的人群细胞系中学习批量转录组谱和药物基因组学信息,并将知识转移到推断个体细胞的药物疗效。结果表明,从临床前细胞系中学习知识,适用于推断药物暴露前具有不同药物敏感性的预先存在的细胞亚群。此外,该模型为药物组合提供了新的视角。可以观察到耐药亚群对其他药物敏感(例如,JHU006 的一部分对 Vorinostat 耐药,而对 Gefitinib 敏感);这种发现与先前在几种癌症类型中报道的药物组合(Gefitinib + Vorinostat)策略相吻合。鉴定的药物敏感性生物标志物揭示了对肿瘤异质性和细胞水平治疗的深入了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/346c/10104628/dd6c94cfc891/ADVS-10-2204113-g004.jpg

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