5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling

Deepak K. Singh, Saul Carcamo, Eduardo F. Farias, Dan Hasson, Wei Zheng, Dan Sun, Xin Huang, Julie Cheung, Ana Rita Nobre, Nupura Kale, Maria Soledad Sosa, Emily Bernstein, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Disseminated cancer cells (DCCs) in secondary organs can remain dormant for years to decades before reactivating into overt metastasis. Microenvironmental signals leading to cancer cell chromatin remodeling and transcriptional reprogramming appear to control onset and escape from dormancy. Here, we reveal that the therapeutic combination of the DNA methylation inhibitor 5-azacytidine (AZA) and the retinoic acid receptor ligands all-trans retinoic acid (atRA) or AM80, an RARα-specific agonist, promotes stable dormancy in cancer cells. Treatment of head and neck squamous cell carcinoma (HNSCC) or breast cancer cells with AZA+atRA induces a SMAD2/3/4-dependent transcriptional program that restores transforming growth factor β (TGF-β)-signaling and anti-proliferative function. Significantly, either combination, AZA+atRA or AZA+AM80, strongly suppresses HNSCC lung metastasis formation by inducing and maintaining solitary DCCs in a SMAD4+/NR2F1+ non-proliferative state. Notably, SMAD4 knockdown is sufficient to drive resistance to AZA+atRA-induced dormancy. We conclude that therapeutic doses of AZA and RAR agonists may induce and/or maintain dormancy and significantly limit metastasis development.

Original languageEnglish
Article number112560
JournalCell Reports
Volume42
Issue number6
DOIs
StatePublished - 27 Jun 2023

Keywords

  • CP: Cancer
  • CP: Cell biology
  • disseminated cancer cell
  • dormancy
  • enhancers
  • metastasis
  • transcriptional reprogramming

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