EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer
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44321_2025_Article_289.pdf
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Author(s)
Tessier, Camille E.
Derrien, Jennifer
Dupuy, Aurore M. M.
Pelé, Thomas
Moquet, Martin
Roul, Julie
Douillard, Elise
El Harrif, Camille
Pinson, Xavier
Le Gallo, Matthieu
Date Issued
August 26, 2025
Journal
EMBO Molecular Medicine
Publisher
Nature Publishing Group UK
Citation
Anne-Pierre Morel, Maria Ouzounova, Understanding cancer cell plasticity: EMT, respecialisation, and therapeutic opportunities, EMBO Molecular Medicine, 10.1038/s44321-025-00288-2, 17, 10, (2531-2532), (2025).
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Final published version
Abstract
Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial–mesenchymal transition (EMT). However, EMT in human cancer therapeutic response remains poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NFκB-induced cell death. We conclude that an EMT–ciliary signaling axis induces chemoresistance in quasi-mesenchymal ciliated stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/s44321-025-00289-1
