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Cell Chem Biol. 2016 Nov 17;23(11):1428-1438. doi: 10.1016/j.chembiol.2016.09.013. Epub 2016 Oct 27.

Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids.

Author information

1
Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden. Electronic address: wojciech.senkowski@medsci.uu.se.
2
Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
3
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, 17176 Solna, Sweden.
4
Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, 75185 Uppsala, Sweden.
5
Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden. Electronic address: marten.fryknas@medsci.uu.se.

Abstract

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.

KEYWORDS:

3D culture; L1000; OXPHOS; gene expression profiling; high-throughput screening; mevalonate pathway; mitochondria; spheroids; statins; transcriptomics

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PMID:
27984028
DOI:
10.1016/j.chembiol.2016.09.013
[Indexed for MEDLINE]
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