2. Academic Validation
  3. An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy

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

  • J Exp Med. 2022 Jan 3;219(1):e20210836. doi: 10.1084/jem.20210836.
Bassem D Khalil 1 2,  Roberto Sanchez 3 4,  Tasrina Rahman 1 5,  Carolina Rodriguez-Tirado 3,  Stefan Moritsch 1,  Alba Rodriguez Martinez 1,  Brett Miles 5,  Eduardo Farias 1,  Mihaly Mezei 3,  Ana Rita Nobre 1,  Deepak Singh 1,  Nupura Kale 3,  Karl Christoph Sproll 6,  Maria Soledad Sosa 3 7,  Julio A Aguirre-Ghiso 1 5 8 9 7
Affiliations

Affiliations

  • 1 Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 2 Western Atlantic University School of Medicine, Plantation, FL.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 4 Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 5 Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 6 Department of Oral, Maxillofacial and Plastic Facial Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
  • 7 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 8 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 9 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
PMID: 34812843 DOI: 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.

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