EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer
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.
Authors
- Peggy Suzanne (ORCID: https://orcid.org/0000-0002-6080-8306)
- Elise Douillard
- Robert A. Weinberg (ORCID: https://orcid.org/0000-0002-0895-3557)
- Philippe Juin (ORCID: https://orcid.org/0000-0002-4997-3888)
- Florence Godey (ORCID: https://orcid.org/0000-0001-8276-9806)
- Vincent J. Guen
- Claude Prigent (ORCID: https://orcid.org/0000-0001-8515-8699)
- Thomas Pelé
- Patrick Dallemagne (ORCID: https://orcid.org/0000-0002-4845-615X)
- Eloïse M. Grasset (ORCID: https://orcid.org/0000-0001-9857-582X)
- Xavier Pinson (ORCID: https://orcid.org/0000-0003-0773-5061)
- Mario Campone (ORCID: https://orcid.org/0000-0002-5196-5908)
- Aurore M. M. Dupuy
- Éric Letouzé (ORCID: https://orcid.org/0000-0002-6369-2839)
- Julie Roul
- Jacqueline A. Lees (ORCID: https://orcid.org/0000-0001-9451-2194)
- Patrick Tas
- Jennifer Derrien
- Matthieu Le Gallo (ORCID: https://orcid.org/0000-0001-9085-8155)
- Camille El Harrif
- Martin Moquet
- Roselyne Viel
- Camille E. Tessier
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Rennes 2 (FR)
- Oncogenesis Stress Signaling (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- Normandie Université (FR)
- Centre Eugène Marquis (FR)
- Institut Génétique Nantes Atlantique (FR)
- Precision Research (United States) (US)
- Whitehead Institute for Biomedical Research (US)
- Structure Fédérative de Recherche en Biologie et Santé de Rennes (FR)
- Université de Rennes (FR)
- Massachusetts Institute of Technology (US)
- Nantes Université (FR)
- Université de Caen Normandie (FR)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s44321-025-00289-1
- Citations
- 3
- Primary Topic
- Hedgehog Signaling Pathway Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Fondation de France
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- Cancéropôle Grand Ouest
- Conseil Régional des Pays de la Loire