RT Journal Article
SR Electronic
T1 Resolving drug effects in patient-derived cancer cells links organoid responses to genome alterations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 124446
DO 10.1101/124446
A1 Julia Neugebauer
A1 Franziska M. Zickgraf
A1 Jeongbin Park
A1 Steve Wagner
A1 Xiaoqi Jiang
A1 Katharina Jechow
A1 Kortine Kleinheinz
A1 Umut H. Toprak
A1 Marc A. Schneider
A1 Michael Meister
A1 Saskia Spaich
A1 Marc Sütterlin
A1 Matthias Schlesner
A1 Andreas Trumpp
A1 Martin Sprick
A1 Roland Eils
A1 Christian Conrad
YR 2017
UL http://biorxiv.org/content/early/2017/04/06/124446.abstract
AB Cancer drug screening in patient-derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy-based assay to resolve drug-induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug-induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests.