Identifying multiscale translational safety biomarkers using a network-based systems approach
Giulia Callegaro,
Johannes P. Schimming,
Janet Piñero González,
Steven J. Kunnen,
Lukas Wijaya,
Panuwat Trairatphisan,
Linda van den Berk,
Kim Beetsma,
Laura I. Furlong,
Jeffrey J. Sutherland,
Jennifer Mollon,
James L. Stevens,
Bob van de Water
Affiliations
Giulia Callegaro
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Johannes P. Schimming
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Janet Piñero González
Hospital del Mar Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain
Steven J. Kunnen
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Lukas Wijaya
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Panuwat Trairatphisan
AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany
Linda van den Berk
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Kim Beetsma
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands
Laura I. Furlong
Hospital del Mar Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain
Jeffrey J. Sutherland
Novartis Institutes for Biomedical Research, Cambridge, MA, USA
Jennifer Mollon
AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany
James L. Stevens
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands; Corresponding author
Bob van de Water
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands; Corresponding author
Summary: 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.
