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FASEB J. 2019 May 30:fj201802603RR. doi: 10.1096/fj.201802603RR. [Epub ahead of print]

Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.

Author information

1
Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
2
Biotechnology Center (BIOTEC), Technische Universität Dresden, Dresden, Germany.
3
Biomedical Cybernetics Group, Department of Physics, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Center for Systems Biology Dresden (CSBD), Technische Universität Dresden, Dresden, Germany.
4
Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
5
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
6
German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom.
8
Department of Neurology, Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, USA.
9
Innate Repair, London, United Kingdom.
10
Center for Regenerative Therapies Dresden, Dresden, Germany.
11
B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Dresden, Germany.
12
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
13
Stroke Unit, Department of Neurology, Stroke Center and the Peritz and Chantal Sheinberg Cerebrovascular Research Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
14
First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Athens, Greece.
15
Aghia Sophia Children's Hospital, Athens, Greece.
16
Brain Bio-Inspired Computing (BBC) Lab, IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy.

Abstract

Cancer cells can switch between signaling pathways to regulate growth under different conditions. In the tumor microenvironment, this likely helps them evade therapies that target specific pathways. We must identify all possible states and utilize them in drug screening programs. One such state is characterized by expression of the transcription factor Hairy and Enhancer of Split 3 (HES3) and sensitivity to HES3 knockdown, and it can be modeled in vitro. Here, we cultured 3 primary human brain cancer cell lines under 3 different culture conditions that maintain low, medium, and high HES3 expression and characterized gene regulation and mechanical phenotype in these states. We assessed gene expression regulation following HES3 knockdown in the HES3-high conditions. We then employed a commonly used human brain tumor cell line to screen Food and Drug Administration (FDA)-approved compounds that specifically target the HES3-high state. We report that cells from multiple patients behave similarly when placed under distinct culture conditions. We identified 37 FDA-approved compounds that specifically kill cancer cells in the high-HES3-expression conditions. Our work reveals a novel signaling state in cancer, biomarkers, a strategy to identify treatments against it, and a set of putative drugs for potential repurposing.-Poser, S. W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C., Gruetzmann, K., Adasme, M. F., Stodolak, S., Nikolakopoulou, P., Park, D. M., Mcintyre, A., Lesche, M., Dahl, A., Lennig, P., Bornstein, S. R., Schroeck, E., Klink, B., Leker, R. R., Bickle, M., Chrousos, G. P., Schroeder, M., Cannistraci, C. V., Guck, J., Androutsellis-Theotokis, A. Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.

KEYWORDS:

brain tumor; drug repurposing; glioblastoma; glioma; signal transduction

PMID:
31145643
DOI:
10.1096/fj.201802603RR

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