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. 2025 Aug 26.
doi: 10.1038/s44321-025-00289-1. Online ahead of print.

EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer

Camille E Tessier #  1 , Jennifer Derrien #  1 , Aurore M M Dupuy  1 , Thomas Pelé  1 , Martin Moquet  1 , Julie Roul  1   2 , Elise Douillard  1 , Camille El Harrif  1 , Xavier Pinson  3 , Matthieu Le Gallo  4   5 , Florence Godey  4   5 , Patrick Tas  4   5 , Roselyne Viel  6 , Eloïse Grasset  1 , Claude Prigent  7 , Éric Letouzé  8 , Peggy Suzanne  9 , Patrick Dallemagne  9 , Mario Campone  1   2 , Robert A Weinberg  10   11   12 , Jacqueline A Lees  11   12 , Philippe P Juin  1   2 , Vincent J Guen  13   14
Affiliations
Free article

EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer

Camille E Tessier et al. EMBO Mol Med. .
Free article

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.

Keywords: EMT; Primary cilia; Therapeutic Resistance; Triple-Negative Breast Cancer.

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Conflict of interest statement

Disclosure and competing interests statement. A Patient application #EP24199133.0 named INHIBITOR OF CILIOGENESIS FOR USE IN A METHOD OF PREVENTING THERAPEUTIC RESISTANCE IN CANCER was filed by Inserm Transfert.

References

    1. Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB et al (2021) Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529–1541 - PubMed
    1. Bhatia S, Kramer M, Russo S, Naik P, Arun G, Brophy K, Andrews P, Fan C, Perou CM, Preall J et al (2022) Patient-derived triple-negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics. Cancer Res 82:1174–1192 - PubMed - PMC
    1. Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, Gould SE, de Sauvage FJ (2018) A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature 562:429–433 - PubMed
    1. Bierie B, Pierce SE, Kroeger C, Stover DG, Pattabiraman DR, Thiru P, Liu Donaher J, Reinhardt F, Chaffer CL, Keckesova Z et al (2017) Integrin-beta4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc Natl Acad Sci USA 114:E2337–E2346 - PubMed - PMC
    1. Bonnefoi H, Litiere S, Piccart M, MacGrogan G, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Moldovan C et al (2014) Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial. Ann Oncol 25:1128–1136 - PubMed - PMC

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