A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alice Dini, Harlan Barker, Emilia Piki, Subodh Sharma, Juuli Raivola, Astrid Murumägi, Daniela Ungureanu
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Abstract

The gene-regulatory dynamics governing drug responses in cancer are yet to be fully understood. Here, we report a pipeline capable of producing high-throughput pharmacotranscriptomic profiling through live-cell barcoding using antibody–oligonucleotide conjugates. This pipeline combines drug screening with 96-plex single-cell RNA sequencing. We show the potential of this approach by exploring the heterogeneous transcriptional landscape of primary high-grade serous ovarian cancer (HGSOC) cells after treatment with 45 drugs, with 13 distinct classes of mechanisms of action. A subset of phosphatidylinositol 3-OH kinase (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) inhibitors induced the activation of receptor tyrosine kinases, such as the epithelial growth factor receptor (EGFR), and this was mediated by the upregulation of caveolin 1 (CAV1). This drug resistance feedback loop could be mitigated by the synergistic action of agents targeting PI3K–AKT–mTOR and EGFR for HGSOC with CAV1 and EGFR expression. Using this workflow could enable the personalized testing of patient-derived tumor samples at single-cell resolution.

Abstract Image

用于药物发现的多重单细胞 RNA-Seq 药物转录组学管道
癌症药物反应的基因调控动态尚未完全明了。在这里,我们报告了一种利用抗体-寡核苷酸共轭物进行活细胞条形码分析的方法,该方法能够进行高通量药物转录组学分析。该方法将药物筛选与 96 复式单细胞 RNA 测序相结合。我们通过探索原发性高级别浆液性卵巢癌(HGSOC)细胞在接受 45 种药物治疗后的异质性转录图谱,展示了这种方法的潜力,这些药物有 13 种不同的作用机制。磷脂酰肌醇3-OH激酶(PI3K)、蛋白激酶B(AKT)和哺乳动物雷帕霉素靶标(mTOR)抑制剂诱导了受体酪氨酸激酶(如上皮生长因子受体(EGFR))的活化,这是由洞穴素1(CAV1)的上调介导的。对于有 CAV1 和表皮生长因子受体表达的 HGSOC,靶向 PI3K-AKT-mTOR 和表皮生长因子受体的药物的协同作用可以缓解这种耐药反馈回路。使用这种工作流程可以对患者来源的肿瘤样本进行单细胞分辨率的个性化检测。
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来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
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