An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Article numbere20210836
JournalJournal of Experimental Medicine
Volume219
Issue number1
DOIs
StatePublished - Nov 23 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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