PO.BCS01.02 · 生物信息与计算
利用Multiomics2Targets2工作流程鉴定肿瘤特异性膜靶点、疗法及用于实验验证的匹配细胞系
Identifying tumor-specific membrane targets, therapeutics, and matching cell lines for experimental validation with the Multiomics2Targets2 workflow
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摘要 Abstract
中文摘要
癌症患者肿瘤多组学分析的快速进展为个体化靶点鉴定开辟了一系列可能性。为此，我们此前开发了Multiomics2Targets，一个鉴定肿瘤特异性膜蛋白的平台。这些肿瘤特异性膜靶点在输入的RNA-seq肿瘤样本中高表达，而基于由GTEx、Tabula Sapiens和ARCHS4构建的转录组学分析图谱，在数百种正常组织和细胞类型中低表达。为进一步优先筛选所鉴定的靶点以开展体外和体内实验，我们利用来自癌症细胞系百科全书(CCLE)和癌症依赖性图谱(DepMap)的数据升级了Multiomics2Targets工作流程。我们从CCLE中鉴定同样表达所鉴定靶点的相关细胞系，并从DepMap中检查所鉴定靶点被敲低时对细胞系增殖的影响。我们还通过整合来自六个数据库的Connectivity Mapping资源，向工作流程中加入了药物预测。此外，更新后的Multiomics2Targets工作流程可应用于单细胞RNA-seq数据，或者可将bulk RNA-seq样本反卷积为类单细胞谱。升级后的工作流程还应用ChEA-KG和Enrichr工具来鉴定富集的转录因子调控子网络、通路、相关表型及其他富集条目。所得的图表被汇编成一份自动生成的报告，其中包括引言、方法、结果和结论。我们通过为来自Clinical Proteomic Tumor Analysis Consortium 3项目的胰腺腺癌肿瘤发现肿瘤亚型特异性细胞表面靶点、富集通路、下调性化学扰动及最相似细胞系，展示了升级后工作流程的实用性。我们通过文献检索验证了若干排名靠前的靶点和化学扰动，并为未来的体外和体内验证实验提出了新的靶点、疗法和细胞系。更新后的药物与靶点发现工作流程被编入了一款名为Multiomics2Targets2(M2T2)的新软件应用中。
查看英文原文 English abstract
Rapid advancements in the multi-omics profiling of tumors from cancer patients have opened up a range of possibilities for personalized target identification. To this end, we previously developed Multiomics2Targets, a platform that identifies tumor-specific membrane proteins. The tumor-specific membrane targets are highly expressed in the input RNA-seq tumor samples while lowly expressed in hundreds of normal tissues and cell types based on transcriptomics profiling atlases created from GTEx, Tabula Sapiens, and ARCHS4. To further prioritize the identified targets for conducting in-vitro and in-vivo experiments, we upgraded the Multiomics2Targets workflow with data from the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Dependency Map (DepMap). From CCLE we identify correlated cell lines that also express the identified targets, and from DepMap we examine the effects of the identified targets on cell line proliferation when knocked down. We also added to the workflow drug predictions by integrating Connectivity Mapping resources from six databases. Additionally, the updated Multiomics2Targets workflow can be applied to single cell RNA-seq data, or bulk RNA-seq samples can be deconvoluted into single-cell-like profiles. The upgraded workflow also applies the tools ChEA-KG and Enrichr to identify enriched transcription factor regulatory subnetworks, pathways, associated phenotypes, and other enriched terms. The resulting figures and tables are compiled into an automatically generated report which includes introduction, methods, results, and conclusions. We demonstrate the utility of the upgraded workflow by discovering tumor subtype-specific cell-surface targets, enriched pathways, down-regulating chemical perturbations, and most similar cell lines for pancreatic adenocarcinoma tumors from the Clinical Proteomic Tumor Analysis Consortium 3 project. We validate several highly ranked targets and chemical perturbations by literature search, as well as suggest novel targets, therapeutics, and cell lines for future in-vitro and in-vivo validation experiments. The updated drug and target discovery workflow is encoded into a new software application called Multiomics2Targets2 (M2T2).
利益披露 Disclosure
A. I. Byrd, None..
L. D. Taub, None..
A. Ma'ayan, None.