An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy
Open Access
- 23 November 2021
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 219 (1)
- https://doi.org/10.1084/jem.20210836
Abstract
We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.Funding Information
- National Institutes of Health
- National Cancer Institute (CA109182, CA216248, CA218024, CA196521)
- Samuel Waxman Cancer Research Foundation
- BioAccelerate NYC–NYC Partnership Fund
- HiberCell
- National Cancer Institute (CA201054)
- Susan G. Komen (CCR17483357)
- Melanoma Research Alliance (401181)
- National Cancer Institute (CA078207)
- Portuguese Foundation for Science and Technology (SFRH/BD/100380/2014)
- Deutsche Krebshilfe (109600)
- National Institutes of Health (S10OD018522, S10OD026880)
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