Network integration and modelling of dynamic drug responses at multi-omicslevels.

Selevsek, Nathalie and Caiment, Florian and Nudischer, Ramona and Gmuender,Hans and Agarkova, Irina and Atkinson, Francis L and Bachmann, Ivo andBaier, Vanessa and Barel, Gal and Bauer, Chris and Boerno, Stefan and Bosc,Nicolas and Clayton, Olivia and

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

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October, 2020


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