An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy
| Autor: | Karl Christoph Sproll, Julio A. Aguirre-Ghiso, Deepak K. Singh, Carolina Rodriguez-Tirado, Ana Rita Nobre, Maria Soledad Sosa, Eduardo F. Farias, Alba Rodriguez Martinez, Mihaly Mezei, Bassem Khalil, Roberto Sanchez, Tasrina Rahman, Nupura Kale, Brett A. Miles, Stefan Moritsch |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Agonist
Lung Neoplasms medicine.drug_class Immunology Mice Nude Kaplan-Meier Estimate Biology Metastasis Metastasis Suppression Small Molecule Libraries Transcription (biology) Cell Line Tumor medicine Immunology and Allergy Animals Humans RNA-Seq Mice Inbred BALB C COUP Transcription Factor I Molecular Structure Neural crest medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic HEK293 Cells Nuclear receptor Head and Neck Neoplasms Cancer cell Cancer research Carcinoma Squamous Cell Dormancy Female |
| Zdroj: | The Journal of experimental medicine. 219(1) |
| ISSN: | 1540-9538 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|