Abstract 1090: NR2F1 coordinates a dormancy program by inducing low self-renewal capacity and a repressive chromatin state.

Abstract

Abstract Clinical studies have shown that solitary disseminated tumor cells (DTCs) in distant organs can be detected years after treatment of primary tumors. This has led to the notion that these solitary DTCs must enter a non-proliferative state or cellular dormancy. This may also hold true for residual tumor cells left behind in loco-regional sites after surgery. Unfortunately, the mechanisms regulating the timing of dormancy and the awakening of DTCs to fuel recurrences are unknown. Similarly, tools to stably induce dormancy of residual disease are unavailable. Here we show that transient differentiation signals propagated by treatment (3-4 days) with retinoic acid (atRA) along with the DNA demethylating agent 5-Aza-C reprogrammed malignant cells into dormancy for remarkably long periods of time (weeks). This reprogramming was associated with upregulation of the orphan nuclear receptor NR2F1/COUP-TF1 and other genes included in a gene signature previously linked to dormancy and late metastasis in breast patients. Importantly, the reprogramming was dependent on NR2F1, which is also silenced in breast and HNSCC tumors, cell lines and mouse cancer models. NR2F1-induced dormancy was associated with a global repressive chromatin state characterized by a H3K27-/K9-me3high/H3K4-me3/H3K27aclow profile. In both breast and HNSCC models NR2F1 blocked self-renewal extinguishing tumor initiating cell subpopulations. Tracking label retaining H2B-GFP cells, gain and loss of function studies showed that NR2F1-induced quiescence occurs via upregulation of SOX9, RARβ and CDK inhibitors. Importantly, inducible shRNAmir-mediated knock down of NR2F1 revealed that it mediates dormancy of occult loco-regional, spleen and lung DTCs, but not of dormant bone marrow DTCs. We conclude that the ability of NR2F1 to limit self-renewal and promote quiescence is key to dormancy induction. Manipulation of such mechanisms via epigenetic and differentiation therapies might represent a strategy to generate induced dormant cancer cells (iDCs) and maintain or eliminate asymptomatic residual disease. Citation Format: Maria S. Sosa, Yeriel Estrada, Falguni Parikh, Almudena Bosch Gutierrez, Yang Zheng, Paloma Bragado, Esther Ekpin, Ajish George, Eduardo Farias, Julio Aguirre-ghiso. NR2F1 coordinates a dormancy program by inducing low self-renewal capacity and a repressive chromatin state. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1090. doi:10.1158/1538-7445.AM2013-1090