Identifying multiscale translational safety biomarkers using a network-based systems approach

iScience, vol. 26, pp. 106094

Abstract

Animal testing is the current standard for drug and chemicals safety assessment, but hazards translation to human is uncertain. Human in vitro models can address the species translation but might not replicate in vivo complexity. Herein, we propose a network-based method addressing these translational multiscale problems that derives in vivo liver injury biomarkers applicable to in vitro human early safety screening. We applied weighted correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset to obtain co-regulated gene clusters (modules). We identified modules statistically associated with liver pathologies, including a module enriched for ATF4-regulated genes as associated with the occurrence of hepatocellular single-cell necrosis, and as preserved in human liver in vitro models. Within the module, we identified TRIB3 and MTHFD2 as a novel candidate stress biomarkers, and developed and used BAC-eGFPHepG2 reporters in a compound screening, identifying compounds showing ATF4-dependent stress response and potential early safety signals.

Authors 13

1. Giulia Callegaro Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

2. Johannes P. Schimming Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

3. Janet Piñero

   Universitat Pompeu Fabra · Hospital del Mar Research Institute

   Affiliation as printed

   Hospital del Mar Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain

4. Steven J. Kunnen Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

5. Lukas S. Wijaya Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

6. Panuwat Trairatphisan

   AbbVie (Germany)

   Affiliation as printed

   AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany

7. Linda van den Berk Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

8. Kim Beetsma Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

9. Laura Ines Furlong

   Universitat Pompeu Fabra · Hospital del Mar Research Institute

   Affiliation as printed

   Hospital del Mar Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain

10. Jeffrey J. Sutherland
    Affiliation as printed

    Novartis Institutes for Biomedical Research, Cambridge, MA, USA

11. Jennifer E. Mollon

    AbbVie (Germany)

    Affiliation as printed

    AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany

12. James L. Stevens corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

13. Bob van de Water corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands