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 Hubers; 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^*, Karianne Schuurman, Isabel Mayayo-Peralta, Anna G Manjón, Mark Buijs, Selçuk Yavuz, Max D Wellenstein, Alejandro Barrera, Kim Monkhorst, Anne Hubers, 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 for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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
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
Externally published	Yes

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.

Copyright:
© 2021. The Author(s).

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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., Hubers, 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). 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.",

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 Hubers 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. Copyright: {\textcopyright} 2021. The Author(s).",

year = "2021",

month = jul,

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

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Prekovic, S, Schuurman, K, Mayayo-Peralta, I, Manjón, AG, Buijs, M, Yavuz, S, Wellenstein, MD, Barrera, A, Monkhorst, K, Hubers, 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. 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 - Hubers, 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. 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.

U2 - 10.1038/s41467-021-24537-3

DO - 10.1038/s41467-021-24537-3

M3 - Article

C2 - 34272384

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Bibliographical note

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