Network integration and modelling of dynamic drug responses at multi-omics levels

• DOI: 10.1038/s42003-020-01302-8
• Publication Date: 2020-10-15T10:07:55Z
• Authors: Nathalie Selevsek; Florian Caiment; Ramona Nudischer; Hans Gmuender; Irina Agarkova; Francis L. Atkinson; Ivo Bachmann; Vanessa Baier; Gal Barel; Chris Bauer; Stefan Boerno; Nicolas Bosc; Olivia Clayton; Henrik Cordes; Sally Deeb; Stefano Gotta; Patrick Guye; Anne Hersey; Fiona M. I. Hunter; Laura Kunz; Alex Lewalle; Matthias Lienhard; Jort Merken; Jasmine Minguet; Bernardo Oliveira; Carla Pluess; Ugis Sarkans; Yannick Schrooders; Johannes Schuchhardt; Ines Smit; Christoph Thiel; Bernd Timmermann; Marcha Verheijen; Timo Wittenberger; Witold Wolski; Alexandra Zerck; Stephane Heymans; Lars Kuepfer; Adrian Roth; Ralph Schlapbach; Steven Niederer; Ralf Herwig; Jos Kleinjans
• Keywords: Cardiotoxicity; Daunorubicin

Abstract Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular drug safety. This can be realized by integrating the activities networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms anthracycline cardiotoxicity measured four different drugs (doxorubicin, epirubicin, idarubicin daunorubicin). Dynamic analysis at vivo exposure levels reveal a 175 disease-associated proteins identify common modules vitro, related mitochondrial sarcomere function as well remodeling extracellular matrix. These vitro-identified are transferable evaluated biopsies cardiomyopathy patients. our knowledge most comprehensive study on demonstrates reproducible workflow serves template detecting complex omics data.