Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids. Issue 11 (17th November 2016)

• Record Type: Journal Article
• Authors: Senkowski, Wojciech; Jarvius, Malin; Rubin, Jenny; Lengqvist, Johan; Gustafsson, Mats G.; Nygren, Peter; Kultima, Kim; Larsson, Rolf; Fryknäs, Mårten
• Is Part Of: Cell chemical biology. Volume 23:Issue 11(2016)
• Page Start: 1428
• Page End: 1438
• Publication Date: 2016-11-17
• Subjects: OXPHOS -- spheroids -- statins -- mevalonate pathway -- 3D culture -- gene expression profiling -- high-throughput screening -- L1000 -- transcriptomics -- mitochondria; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.09.013
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses. As a proof of concept, we examined drug responses of quiescent cancer cells to oxidative phosphorylation (OXPHOS) inhibitors. Use of multicellular tumor spheroids led to discovery that the mevalonate pathway is upregulated in quiescent cells during OXPHOS inhibition, and that OXPHOS inhibitors and mevalonate pathway inhibitors were synergistically toxic to quiescent spheroids. This work illustrates how 3D cellular models yield functional and mechanistic insights not accessible via 2D cultures. Graphical Abstract: Highlights: Novel approach to high-throughput gene expression profiling in 3D cell cultures Dataset of over 1, 000 gene expression profiles available to the scientific community Quiescent cancer cells upregulate mevalonate pathway genes upon OXPHOS inhibition OXPHOS inhibitors and statins are synergistically toxic to quiescent cancer cells Abstract : Large-scale gene expression profiling has been applied in monolayer cells but not in complex three-dimensional cultures. Senkowski et al. present a novel procedure for high-throughput gene expression profiling in multicellular tumor spheroids to identify context-dependent drug responses.