{"doi":"10.1101/2021.01.30.428967","title":"A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy","abstract":"A bstract Disseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo . The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor β (RARβ) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1 hi /p27 hi /Ki-67 lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216382,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":469442,"name":"Roberto Sánchez","orcid":"0000-0002-7805-3597","position":1,"is_corresponding":false},{"id":637416,"name":"Tasrina Rahman","orcid":null,"position":2,"is_corresponding":false},{"id":636375,"name":"Carolina Rodríguez-Tirado","orcid":"0000-0002-3853-7909","position":3,"is_corresponding":false},{"id":636376,"name":"Stefan Moritsch","orcid":"0000-0002-1849-1616","position":4,"is_corresponding":false},{"id":636377,"name":"Alba Rodríguez‐Martínez","orcid":"0000-0002-9652-1550","position":5,"is_corresponding":false},{"id":637417,"name":"Brett A. Miles","orcid":null,"position":6,"is_corresponding":false},{"id":619037,"name":"Eduardo Farias","orcid":"0000-0003-4811-7550","position":7,"is_corresponding":false},{"id":404107,"name":"Mihaly Mezei","orcid":"0000-0003-0294-4307","position":8,"is_corresponding":false},{"id":579399,"name":"Julie F. Cheung","orcid":"0000-0003-1346-0930","position":9,"is_corresponding":false},{"id":619036,"name":"Ana Rita Nobre","orcid":"0000-0002-5509-904X","position":10,"is_corresponding":false},{"id":636378,"name":"Nupura Kale","orcid":"0000-0002-3185-8646","position":11,"is_corresponding":false},{"id":812791,"name":"Karl Christoph Sproll","orcid":null,"position":12,"is_corresponding":false},{"id":636380,"name":"María Soledad Sosa","orcid":"0000-0001-8783-3520","position":13,"is_corresponding":false},{"id":105283,"name":"Julio A. Aguirre‐Ghiso","orcid":"0000-0002-6694-6507","position":14,"is_corresponding":false},{"id":604634,"name":"Bassem D. Khalil","orcid":"0000-0001-8699-6950","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T23:53:11.245932Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}