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.
An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy
Disclosures: J.A. Aguirre-Ghiso reported grants from HiberCell LLC during the conduct of the study; grants from HiberCell LLC outside the submitted work; and is a HiberCell LLC co-founder, consultant, and scientific advisory board member. No other disclosures were reported.
D. Singh and J.A. Aguirre-Ghiso’s present address is Department of Cell Biology, Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY.
- Award Id(s): CA109182,CA216248,CA218024,CA196521
- Award Id(s): CA201054
- Award Id(s): CCR17483357
- Award Id(s): 401181
- Award Id(s): CA078207
- Award Id(s): SFRH/BD/100380/2014
- Award Id(s): 109600
- Award Id(s): S10OD018522,S10OD026880
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Bassem D. Khalil, Roberto Sanchez, Tasrina Rahman, Carolina Rodriguez-Tirado, Stefan Moritsch, Alba Rodriguez Martinez, Brett Miles, Eduardo Farias, Mihaly Mezei, Ana Rita Nobre, Deepak Singh, Nupura Kale, Karl Christoph Sproll, Maria Soledad Sosa, Julio A. Aguirre-Ghiso; An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy. J Exp Med 3 January 2022; 219 (1): e20210836. doi: https://doi.org/10.1084/jem.20210836
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