NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes

Maria Soledad Sosa; Falguni Parikh; Alexandre Gaspar Maia; Yeriel Estrada; Almudena Bosch; Paloma Bragado; Esther Ekpin; Ajish George; Yang Zheng; Hung Ming Lam; Colm Morrissey; Chi Yeh Chung; Eduardo F. Farias; Emily Bernstein; Julio A. Aguirre-Ghiso

doi:10.1038/ncomms7170

NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes

Maria Soledad Sosa, Falguni Parikh, Alexandre Gaspar Maia, Yeriel Estrada, Almudena Bosch, Paloma Bragado, Esther Ekpin, Ajish George, Yang Zheng, Hung Ming Lam, Colm Morrissey, Chi Yeh Chung, Eduardo F. Farias, Emily Bernstein, Julio A. Aguirre-Ghiso

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178 Scopus citations

Abstract

Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7-18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.

Original language	English
Article number	6170
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7170
State	Published - 30 Jan 2015

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@article{720d62a535a549558940fc8a776257a4,

title = "NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes",

abstract = "Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7-18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.",

author = "Sosa, {Maria Soledad} and Falguni Parikh and Maia, {Alexandre Gaspar} and Yeriel Estrada and Almudena Bosch and Paloma Bragado and Esther Ekpin and Ajish George and Yang Zheng and Lam, {Hung Ming} and Colm Morrissey and Chung, {Chi Yeh} and Farias, {Eduardo F.} and Emily Bernstein and Aguirre-Ghiso, {Julio A.}",

note = "Funding Information: We thank the Bernstein, Farias and Aguirre-Ghiso labs as well as Peter Nelson, Robert L Vessella and Lynda Snyder for useful discussions. This study was supported by Samuel Waxman Cancer Research Foundation Tumor Dormancy Program to J.A.A.-G., E.F.F. and E.B., NIH/National Cancer Institute (CA109182, CA163131), NIEHS (ES017146) and NYSTEM to J.A.A.-G., JJR Foundation and Hirschl/Weill-Caulier Trust Research Award to E.B., DoD-BCRP Grant BC100975 to A.G.M. and DoD-BCRP Grant BC112380 to M.S.S. NIH RC1 CA144825-0 ARRA Challenge, Janssen Research and Development LLC to Peter S Nelson, Robert L. Vessella and Linda Snyder. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jan,

day = "30",

doi = "10.1038/ncomms7170",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes

AU - Sosa, Maria Soledad

AU - Parikh, Falguni

AU - Maia, Alexandre Gaspar

AU - Estrada, Yeriel

AU - Bosch, Almudena

AU - Bragado, Paloma

AU - Ekpin, Esther

AU - George, Ajish

AU - Zheng, Yang

AU - Lam, Hung Ming

AU - Morrissey, Colm

AU - Chung, Chi Yeh

AU - Farias, Eduardo F.

AU - Bernstein, Emily

AU - Aguirre-Ghiso, Julio A.

N1 - Funding Information: We thank the Bernstein, Farias and Aguirre-Ghiso labs as well as Peter Nelson, Robert L Vessella and Lynda Snyder for useful discussions. This study was supported by Samuel Waxman Cancer Research Foundation Tumor Dormancy Program to J.A.A.-G., E.F.F. and E.B., NIH/National Cancer Institute (CA109182, CA163131), NIEHS (ES017146) and NYSTEM to J.A.A.-G., JJR Foundation and Hirschl/Weill-Caulier Trust Research Award to E.B., DoD-BCRP Grant BC100975 to A.G.M. and DoD-BCRP Grant BC112380 to M.S.S. NIH RC1 CA144825-0 ARRA Challenge, Janssen Research and Development LLC to Peter S Nelson, Robert L. Vessella and Linda Snyder. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/1/30

Y1 - 2015/1/30

N2 - Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7-18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.

AB - Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7-18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.

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U2 - 10.1038/ncomms7170

DO - 10.1038/ncomms7170

M3 - Article

C2 - 25636082

AN - SCOPUS:84938626001

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6170

ER -

NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes

Abstract

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