An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy
Bassem D Khalil1,2, Roberto Sanchez3,4, Tasrina Rahman1,5
1Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
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.
Insights
We discovered a new drug that activates the NR2F1 receptor to put cancer cells into dormancy. This approach halts tumor growth and prevents metastasis, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Malignant cells often evade therapy through dormancy.
- Nuclear receptor NR2F1 plays a role in cell fate and proliferation.
Purpose of the Study:
- To discover and characterize an agonist of NR2F1 that induces cancer cell dormancy.
- To evaluate the therapeutic potential of NR2F1 activation in preventing metastasis.
Main Methods:
- Screening for NR2F1 agonists.
- In vitro and in vivo studies using cancer cell lines, patient-derived organoids, and xenograft models.
- CRISPR-Cas9 gene editing to validate NR2F1's role.
- RNA sequencing to analyze transcriptional changes.
Main Results:
- A novel agonist specifically activates NR2F1, increasing its expression and inducing a dormancy program.
- Treatment led to growth arrest in head and neck squamous cell carcinoma (HNSCC) models, including patient-derived organoids and in vivo.
- NR2F1 knockout abolished the dormancy-inducing effect.
- RNA sequencing revealed suppressed cell cycle and mTOR signaling, inhibited metastasis, and induced neural crest lineage program.
- Agonist treatment prevented lung metastasis in mice, with dormant tumor cells maintaining a specific phenotype.
Conclusions:
- NR2F1 agonists can induce a self-sustaining dormancy program in malignant cells.
- This strategy effectively halts tumor growth and prevents metastasis, even after treatment cessation.
- NR2F1 activation represents a promising therapeutic approach to combat cancer progression and metastasis.
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