Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

Stefan Prekovic; Karianne Schuurman; Isabel Mayayo-Peralta; Anna G. Manjón; Mark Buijs; Selçuk Yavuz; Max D. Wellenstein; Alejandro Barrera; Kim Monkhorst; Anne Huber; Ben Morris; Cor Lieftink; Theofilos Chalkiadakis; Ferhat Alkan; Joana Silva; Balázs Győrffy; Liesbeth Hoekman; Bram van den Broek; Hans Teunissen; Donna O. Debets; Tesa Severson; Jos Jonkers; Timothy Reddy; Karin E. de Visser; William Faller; Roderick Beijersbergen; Maarten Altelaar; Elzo de Wit; Rene Medema; Wilbert Zwart

doi:10.1038/s41467-021-24537-3

Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

Stefan Prekovic (Corresponding author), Karianne Schuurman, Isabel Mayayo-Peralta, Anna G. Manjón, Mark Buijs, Selçuk Yavuz, Max D. Wellenstein, Alejandro Barrera, Kim Monkhorst, Anne Huber, Ben Morris, Cor Lieftink, Theofilos Chalkiadakis, Ferhat Alkan, Joana Silva, Balázs Győrffy, Liesbeth Hoekman, Bram van den Broek, Hans Teunissen, Donna O. DebetsTesa Severson, Jos Jonkers, Timothy Reddy, Karin E. de Visser, William Faller, Roderick Beijersbergen, Maarten Altelaar, Elzo de Wit, Rene Medema, Wilbert Zwart (Corresponding author)

Chemical Biology

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Abstract

The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.

Original language	English
Article number	4360
Number of pages	18
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24537-3
Publication status	Published - 16 Jul 2021

Bibliographical note

Funding Information:
This work was funded by the Netherlands Organization for Scientific Research NWO VIDI grant 91716401, an Alpe d’Huzes/KWF Bas Mulder Award, KWF grant #12128, and Oncode Institute. Joana Silva was supported by an EMBO long-term fellowship (ALTF 210-2018). Balázs Győrffy was supported by the NVKP_16-1-2016-0037 grant. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for lab support, the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support, and the NKI mouse intervention unit for performing xenograft experiments. We thank Laurel M. Schunselaar for help with mesothelioma pathological samples; Suzan Stelloo for frequent, and helpful discussions; and Sarah Vahed for proofreading.

Publisher Copyright:
© 2021, The Author(s).

Keywords

Animals
Antineoplastic Agents/pharmacology
Cell Cycle/genetics
Cell Line, Tumor
Cell Proliferation/drug effects
Cell Survival/drug effects
Chromatin/genetics
Chromatin Immunoprecipitation Sequencing
Chromosomal Proteins, Non-Histone/genetics
Cyclin-Dependent Kinase Inhibitor p57/genetics
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic/drug effects
Glucocorticoids/pharmacology
Humans
Imidazoles/pharmacology
Immunohistochemistry
Lung Neoplasms/genetics
Mice
Proteomics
Pyrazines/pharmacology
RNA, Small Interfering
RNA-Seq
Receptor, IGF Type 1/metabolism
Receptors, Glucocorticoid/metabolism
Transcription Factors/genetics
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-24537-3

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Prekovic, S., Schuurman, K., Mayayo-Peralta, I., Manjón, A. G., Buijs, M., Yavuz, S., Wellenstein, M. D., Barrera, A., Monkhorst, K., Huber, A., Morris, B., Lieftink, C., Chalkiadakis, T., Alkan, F., Silva, J., Győrffy, B., Hoekman, L., van den Broek, B., Teunissen, H., ... Zwart, W. (2021). Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer. Nature Communications, 12(1), Article 4360. https://doi.org/10.1038/s41467-021-24537-3

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title = "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer",

abstract = "The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.",

keywords = "Animals, Antineoplastic Agents/pharmacology, Cell Cycle/genetics, Cell Line, Tumor, Cell Proliferation/drug effects, Cell Survival/drug effects, Chromatin/genetics, Chromatin Immunoprecipitation Sequencing, Chromosomal Proteins, Non-Histone/genetics, Cyclin-Dependent Kinase Inhibitor p57/genetics, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic/drug effects, Glucocorticoids/pharmacology, Humans, Imidazoles/pharmacology, Immunohistochemistry, Lung Neoplasms/genetics, Mice, Proteomics, Pyrazines/pharmacology, RNA, Small Interfering, RNA-Seq, Receptor, IGF Type 1/metabolism, Receptors, Glucocorticoid/metabolism, Transcription Factors/genetics, Xenograft Model Antitumor Assays",

author = "Stefan Prekovic and Karianne Schuurman and Isabel Mayayo-Peralta and Manj{\'o}n, {Anna G.} and Mark Buijs and Sel{\c c}uk Yavuz and Wellenstein, {Max D.} and Alejandro Barrera and Kim Monkhorst and Anne Huber and Ben Morris and Cor Lieftink and Theofilos Chalkiadakis and Ferhat Alkan and Joana Silva and Bal{\'a}zs Gy{\H o}rffy and Liesbeth Hoekman and {van den Broek}, Bram and Hans Teunissen and Debets, {Donna O.} and Tesa Severson and Jos Jonkers and Timothy Reddy and {de Visser}, {Karin E.} and William Faller and Roderick Beijersbergen and Maarten Altelaar and {de Wit}, Elzo and Rene Medema and Wilbert Zwart",

note = "Funding Information: This work was funded by the Netherlands Organization for Scientific Research NWO VIDI grant 91716401, an Alpe d{\textquoteright}Huzes/KWF Bas Mulder Award, KWF grant #12128, and Oncode Institute. Joana Silva was supported by an EMBO long-term fellowship (ALTF 210-2018). Bal{\'a}zs Gy{\H o}rffy was supported by the NVKP_16-1-2016-0037 grant. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for lab support, the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support, and the NKI mouse intervention unit for performing xenograft experiments. We thank Laurel M. Schunselaar for help with mesothelioma pathological samples; Suzan Stelloo for frequent, and helpful discussions; and Sarah Vahed for proofreading. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

day = "16",

doi = "10.1038/s41467-021-24537-3",

language = "English",

volume = "12",

journal = "Nature Communications",

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Prekovic, S, Schuurman, K, Mayayo-Peralta, I, Manjón, AG, Buijs, M, Yavuz, S, Wellenstein, MD, Barrera, A, Monkhorst, K, Huber, A, Morris, B, Lieftink, C, Chalkiadakis, T, Alkan, F, Silva, J, Győrffy, B, Hoekman, L, van den Broek, B, Teunissen, H, Debets, DO, Severson, T, Jonkers, J, Reddy, T, de Visser, KE, Faller, W, Beijersbergen, R, Altelaar, M, de Wit, E, Medema, R & Zwart, W 2021, 'Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer', Nature Communications, vol. 12, no. 1, 4360. https://doi.org/10.1038/s41467-021-24537-3

TY - JOUR

T1 - Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

AU - Prekovic, Stefan

AU - Schuurman, Karianne

AU - Mayayo-Peralta, Isabel

AU - Manjón, Anna G.

AU - Buijs, Mark

AU - Yavuz, Selçuk

AU - Wellenstein, Max D.

AU - Barrera, Alejandro

AU - Monkhorst, Kim

AU - Huber, Anne

AU - Morris, Ben

AU - Lieftink, Cor

AU - Chalkiadakis, Theofilos

AU - Alkan, Ferhat

AU - Silva, Joana

AU - Győrffy, Balázs

AU - Hoekman, Liesbeth

AU - van den Broek, Bram

AU - Teunissen, Hans

AU - Debets, Donna O.

AU - Severson, Tesa

AU - Jonkers, Jos

AU - Reddy, Timothy

AU - de Visser, Karin E.

AU - Faller, William

AU - Beijersbergen, Roderick

AU - Altelaar, Maarten

AU - de Wit, Elzo

AU - Medema, Rene

AU - Zwart, Wilbert

N1 - Funding Information: This work was funded by the Netherlands Organization for Scientific Research NWO VIDI grant 91716401, an Alpe d’Huzes/KWF Bas Mulder Award, KWF grant #12128, and Oncode Institute. Joana Silva was supported by an EMBO long-term fellowship (ALTF 210-2018). Balázs Győrffy was supported by the NVKP_16-1-2016-0037 grant. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for lab support, the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support, and the NKI mouse intervention unit for performing xenograft experiments. We thank Laurel M. Schunselaar for help with mesothelioma pathological samples; Suzan Stelloo for frequent, and helpful discussions; and Sarah Vahed for proofreading. Publisher Copyright: © 2021, The Author(s).

PY - 2021/7/16

Y1 - 2021/7/16

N2 - The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.

AB - The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Cell Cycle/genetics

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Cell Survival/drug effects

KW - Chromatin/genetics

KW - Chromatin Immunoprecipitation Sequencing

KW - Chromosomal Proteins, Non-Histone/genetics

KW - Cyclin-Dependent Kinase Inhibitor p57/genetics

KW - Enhancer Elements, Genetic

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Glucocorticoids/pharmacology

KW - Humans

KW - Imidazoles/pharmacology

KW - Immunohistochemistry

KW - Lung Neoplasms/genetics

KW - Mice

KW - Proteomics

KW - Pyrazines/pharmacology

KW - RNA, Small Interfering

KW - RNA-Seq

KW - Receptor, IGF Type 1/metabolism

KW - Receptors, Glucocorticoid/metabolism

KW - Transcription Factors/genetics

KW - Xenograft Model Antitumor Assays

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U2 - 10.1038/s41467-021-24537-3

DO - 10.1038/s41467-021-24537-3

M3 - Article

C2 - 34272384

AN - SCOPUS:85110858166

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4360

ER -

Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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