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Epigenetic regulation of hybrid epithelial-mesenchymal cell states in cancer

Oncogene volume 42, pages 2237–2248 (2023)Cite this article

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Abstract

Epithelial-to-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and gain mesenchymal phenotypes. In cancer, EMT is thought to drive tumor invasion and metastasis. Recent efforts to understand EMT biology have uncovered that cells undergoing EMT attain a spectrum of intermediate “hybrid E/M” states, which exist along an epithelial-mesenchymal continuum. Here, we summarize recent studies characterizing the epigenetic drivers of hybrid E/M states. We focus on the histone-modification writers, erasers, and readers that assist or oppose the canonical hybrid E/M transcription factors that modulate hybrid E/M state transitions. We also examine the role of chromatin remodelers and DNA methylation in hybrid E/M states. Finally, we highlight the challenges of targeting hybrid E/M pharmacologically, and we propose future directions that might reveal the specific and targetable mechanisms by which hybrid E/M drives metastasis in patients.

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Fig. 1: Hybrid E/M states are plastic and phenotypically heterogeneous.
Fig. 2: Hybrid E/M states contribute uniquely to invasion and metastasis.
Fig. 3: Key players in histone-modification biology that contribute to hybrid E/M states.
Fig. 4: Model of the contribution of histone modifications to hybrid E/M state plasticity.

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Acknowledgements

This work was supported by V Foundation V Scholars Award, Cancer Research Institute Technology Impact Award, Cancer Research Foundation Young Investigator Award, Siteman Cancer Center and Barnes Jewish Foundation, American Cancer Society Institutional Research Grant, K08CA237732 (NIH/NCI), R21DE031072 (NIH/NIDCR) (SVP), R01GM123203 (NIH/NIGMS) (RDM), RF1MH117070, RF1MH126723 (NIH/NIMH) (RDM, JDD), R21DE31366 (NIH/NIDCR)(RDM, SVP), and T32HG000045 (NIH/NHGRI) (RAS/MFN). Figures created with Biorender.com.

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Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

    Reilly A. Sample, Marina F. Nogueira, Robi D. Mitra & Sidharth V. Puram

  2. Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Reilly A. Sample, Marina F. Nogueira & Sidharth V. Puram

  3. Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Reilly A. Sample & Robi D. Mitra

  4. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

    Sidharth V. Puram

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RAS and MFN contributed to the conceptualization, content, and revisions of the manuscript. RAS prepared all figures and tables. All authors provided critical review and commentary on the manuscript’s content. SVP and RDM provided oversight and mentorship.

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Sample, R.A., Nogueira, M.F., Mitra, R.D. et al. Epigenetic regulation of hybrid epithelial-mesenchymal cell states in cancer. Oncogene 42, 2237–2248 (2023). https://doi.org/10.1038/s41388-023-02749-9

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