title: Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids.
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.
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden. Electronic address: wojciech.senkowski@medsci.uu.se.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Senkowski
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jarvius
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Rubin
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska University Hospital, 17176 Solna, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lengqvist
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Mats G
authors.initials: MG
authors.lastname: Gustafsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Kim
authors.initials: K
authors.lastname: Kultima
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden. Electronic address: marten.fryknas@medsci.uu.se.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008798:Mevalonic Acid
keywords: 3D culture; L1000; OXPHOS; gene expression profiling; high-throughput screening; mevalonate pathway; mitochondria; spheroids; statins; transcriptomics