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

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

doi:10.1038/ncomms7170

Abstract

Metastases can originate from disseminated tumor cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental 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 programs of quiescence and survival in DTCs.

Highlights

Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation
Because these processes regulate pluripotency and limit proliferation, we investigated whether NR2F1 and these processes were linked to the interconversion between cancer cell dormancy and proliferation
This was corroborated by immunohistochemistry (IHC), immunofluorescence (IF; Fig. 1b, Supplementary Fig. 1a) and western blot (WB), where nuclear NR2F1 protein was three- to fourfolds higher in D-HEp3 cells than in T-HEp3 cells (Fig. 1b)

Summary

Introduction

Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Among the genes in the dormancy signature[3,6,7] we identified NR2F1, an orphan nuclear receptor[8] that induces cell lineage determination in response to signals like retinoic acid (RA)[9], limits induced pluripotent stem cells (iPS) reprogramming[4] and regulates enhancer elements during human neural crest cell differentiation[10]. Restoration of NR2F1 expression using DNAdemethylating agents and activation of RA signalling is sufficient to recapitulate the quiescence programme and induce chromatin changes linked to a durable dormant state These findings break new ground in our understanding of the dormancy mechanisms and identify markers that might pinpoint residual cancer with the ability to escape dormancy

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Results

Conclusion