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

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

  • Nat Chem Biol. 2024 Oct 31. doi: 10.1038/s41589-024-01761-8.
Alice Dini 1,  Harlan Barker 1 2,  Emilia Piki 1,  Subodh Sharma 1,  Juuli Raivola 3,  Astrid Murumägi 4,  Daniela Ungureanu 5 6
Affiliations

Affiliations

  • 1 Disease Networks Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
  • 2 Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
  • 3 Applied Tumor Genomics, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 4 Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 5 Disease Networks Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland. daniela.ungureanu@oulu.fi.
  • 6 Applied Tumor Genomics, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland. daniela.ungureanu@oulu.fi.
PMID: 39482470 DOI: 10.1038/s41589-024-01761-8
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.

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