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

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.

Distinctive properties of metastasis-initiating cells

“…2B). In addition, SOX2 and NANOG have been reported to maintain quiescence programs in DTCs/residual cancer cells and may contribute to metastatic relapse (Sosa et al 2015). Although SOX2, NANOG, OCT4, and KLF4 have been shown to increase metastasis of bladder cancer, breast cancer, lung cancer, and head and neck squamous carcinoma cells (Celia-Terrassa et al 2012;Vaira et al 2013;Lu et al 2014;Habu et al 2015), none of these factors has been specifically studied during metastasis initiation.…”

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…Methylation of promoters of prominent tumor-suppressive genes has been known to enhance aggressive growth at distant sites (64). Sosa et al (13,14) have shown that NR2F1, an orphan nuclear receptor of RA signaling, rendered the dormancy phenotype in vivo by activating global repressive chromatin marks in cancer cells. Interestingly, NR2F1 binds and regulate the SPARC promoter in head and neck squamous cell carcinoma, suggesting a possibility that selection of an indolent clone is dependent on an epigenetic master regulator that changes the expression of prominent gene promoters (13).…”

“…Sosa et al (13,14) have shown that NR2F1, an orphan nuclear receptor of RA signaling, rendered the dormancy phenotype in vivo by activating global repressive chromatin marks in cancer cells. Interestingly, NR2F1 binds and regulate the SPARC promoter in head and neck squamous cell carcinoma, suggesting a possibility that selection of an indolent clone is dependent on an epigenetic master regulator that changes the expression of prominent gene promoters (13). The increased expression of de novo methylase genes DNMT1 and DNMT3b in aggressive cells further supports the notion that epigenetic silencing of the SPARC promoter by methylation may be a potential key for recurrent growth in bone (Fig.…”

“…A high ratio of activated p38 to Erk signals for inhibition of cell proliferation or cellular dormancy, whereas a low ratio reverts the phenotype to the proliferative state (8,11,12). Recently, it was also demonstrated that dormant cells are reprogrammed by epigenetic regulation that leads to a quiescence state (13). In addition, interaction between tumor cells and the stroma, angiogenesis, and immune surveillance of cancer cells are also known to regulate dormancy and recurrence (8,14).…”

“…Although several in vitro models have been described previously, in vivo working models for dormant and recurrent growth have yet to be developed. Recent attempts have characterized syngeneic head and neck squamous cell carcinoma cells (T-Hep and D-Hep) or a pair of breast cancer cell lines (D2.OR and D2A1 cells) that recapitulates dormant growth in vivo (13,(15)(16)(17). However, there is still no appropriate in vivo model that mimics dormancy and recurrence for prostate cancer, especially one that replicates the phenomenon of bone recurrence in patients.…”