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

Poser SW, Otto O, Arps-Forker C, Ge Y, Herbig M, Andree C, Gruetzmann K, Adasme MF, Stodolak S, Nikolakopoulou P, Park DM, Mcintyre A, Lesche M, Dahl A, Lennig P, Bornstein SR, Schroeck E, Klink B, Leker RR, Bickle M, Chrousos GP, Schroeder M, Cannistraci CV, Guck J, Androutsellis-Theotokis A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

The FASEB Journal Federation of American Society of Experimental Biology (FASEB)

Book Volume: 33

Pages Range: 9235-9249

Journal Issue: 8

DOI: 10.1096/fj.201802603RR

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. FASEB J. 33, 9235–9249 (2019). www.fasebj.org.

Authors with CRIS profile

Jochen Guck

Involved external institutions

Technische Universität Dresden DE Germany (DE) Max-Planck-Institut für molekulare Zellbiologie und Genetik / Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) University of Nottingham GB United Kingdom (GB) University of Chicago US United States (USA) (US) Hadassah Medical Center / מרכז רפואי הדסה‎‎ IL Israel (IL) National and Kapodistrian University of Athens GR Greece (GR)

How to cite

APA:

Poser, S.W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C.,... Androutsellis-Theotokis, A. (2019). Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery. The FASEB Journal, 33(8), 9235-9249. https://doi.org/10.1096/fj.201802603RR

MLA:

Poser, Steven W., et al. "Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery." The FASEB Journal 33.8 (2019): 9235-9249.

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