EMT-induced stem cell and mesenchymal programs can be decoupled via cell division and ESRP1-dependent mechanisms
Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and not the mesenchymal signature, induced during EMT, correlates with poor prognosis. All cancer cells with stemness properties exhibit mesenchymal properties, but not all mesenchymal cells exhibit stemness properties. In summary, during EMT the stemness program is controlled by cell division and ESRP1, and this program predicts poor prognosis.
Authors
- W. Fraser Symmans (ORCID: https://orcid.org/0000-0002-1526-184X)
- Tieling Zhou
- Breanna R. Demestichas (ORCID: https://orcid.org/0000-0003-3985-5148)
- Mika Pietilä
- Chunxiao Fu (ORCID: https://orcid.org/0009-0000-6950-5355)
- Suhas Vasaikar (ORCID: https://orcid.org/0000-0001-9763-3899)
- Robiya Joseph (ORCID: https://orcid.org/0000-0003-3214-890X)
- Paul Allegakoen
- Geraldine Raja
- María Castañeda (ORCID: https://orcid.org/0000-0001-5103-337X)
- Alvina Zia
- Nick A. Kuburich (ORCID: https://orcid.org/0000-0002-6720-9680)
- Rama Soundararajan
- Shruti Shah (ORCID: https://orcid.org/0000-0002-0715-3187)
- Chad J. Creighton (ORCID: https://orcid.org/0000-0002-6090-703X)
- Abhijeet Deshmukh (ORCID: https://orcid.org/0000-0002-3587-8812)
- Joanna Joyce Maddela (ORCID: https://orcid.org/0000-0003-0049-404X)
- Claire Gould (ORCID: https://orcid.org/0000-0001-8264-0463)
- Sendurai A. Mani (ORCID: https://orcid.org/0000-0002-5918-4276)
- Petra den Hollander (ORCID: https://orcid.org/0000-0002-4272-1231)
- Jeffrey Chang (ORCID: https://orcid.org/0000-0001-9342-5072)
- Shivangi Agarwal (ORCID: https://orcid.org/0000-0003-3979-3565)
Institutions
- Texas Christian University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Brown University (US)
- University of Illinois Chicago (US)
- Hologic (United States) (US)
- Allen Institute (US)
- Mayo Clinic in Florida (US)
- University of Houston (US)
- University of Pennsylvania (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- iScience
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.isci.2025.114284
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00