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Drug combination screening in multicellular tumor spheroids identifies synthetic lethalities in quiescent cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology Medicinal Chemistry
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-320596OAI: oai:DiVA.org:uu-320596DiVA, id: diva2:1090152
Available from: 2017-04-22 Created: 2017-04-22 Last updated: 2018-01-13
In thesis
1. High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
Open this publication in new window or tab >>High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS.

In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines.

In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1334
Keywords
spheroids, high-throughput screening, nitazoxanide, OXPHOS, gene expression profiling, statins, drug repositioning, 3D cell culture, quiescent cells
National Category
Cell and Molecular Biology Medicinal Chemistry Pharmaceutical Sciences Cancer and Oncology Biomedical Laboratory Science/Technology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology Cell Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-320598 (URN)978-91-554-9921-1 (ISBN)
Public defence
2017-06-10, Hörsal Bertil Hammer (24:K104), Blåsenhus, von Kraemers Allé 1, Uppsala, 09:00 (English)
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Supervisors
Available from: 2017-05-18 Created: 2017-04-22 Last updated: 2018-01-13

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