Mechanisms of active wetting and fluidification in epithelial cell collectives
Tissue-level phase transitions are emerging as a crucial mechanism in tumour development and metastasis. When becoming invasive, epithelial tumours undergo a transition from a solid-like state to a more fluid-like one. Although the contributions of cell adhesions, traction forces and cell migration for such behaviour are known, the exact biophysical and molecular mechanisms controlling these transitions are not fully understood. Here we show that breast cancer cell fluidity is regulated by IRSp53, a protein linking plasma membranes to the cytoskeleton. In both two-dimensional monolayers and three-dimensional spheroids, the depletion of IRSp53 increases fluidity and active wetting of the substrate due to a decrease in intercellular friction and enhanced local cell rearrangements. Molecularly, IRSp53 interacts with the junctional protein Afadin to control global tensile state and active wetting, establishing these proteins as key regulators of epithelial collectives' viscosity in breast cancer tumouroids. In breast cancer patient samples, low IRSp53 expression levels and aberrant localization correlate with worse clinical outcomes. These findings support the broader relevance of IRSp53-regulated mechanics in epithelia and their potential prognostic value in cancer.
Authors
- Brenda J. Green (ORCID: https://orcid.org/0000-0002-4274-0969)
- Nils C. Gauthier (ORCID: https://orcid.org/0000-0003-1260-3477)
- Zeno Lavagnino (ORCID: https://orcid.org/0000-0002-7247-8084)
- Elisa Allievi (ORCID: https://orcid.org/0000-0003-3030-6097)
- Grégoire Lemahieu
- Giovanni Bertalot (ORCID: https://orcid.org/0000-0002-4862-7705)
- Stefano Marchesi (ORCID: https://orcid.org/0000-0003-3973-133X)
- Fabio Giavazzi (ORCID: https://orcid.org/0000-0003-4930-0592)
- Giorgio Scita (ORCID: https://orcid.org/0000-0001-7984-1889)
- Andrea Ghisleni (ORCID: https://orcid.org/0000-0001-8456-5903)
- Dario Parazzoli (ORCID: https://orcid.org/0000-0001-8176-9775)
- Stefano Freddi (ORCID: https://orcid.org/0000-0003-4263-3060)
- Andrew E. Massey (ORCID: https://orcid.org/0000-0001-7688-5501)
- Galina V. Beznoussenko (ORCID: https://orcid.org/0000-0002-1876-4098)
- Serena Magni (ORCID: https://orcid.org/0000-0003-4730-9710)
- Salvatore Pece (ORCID: https://orcid.org/0000-0003-1764-3929)
- Marina Mapelli (ORCID: https://orcid.org/0000-0001-8502-0649)
- Emanuele Martini (ORCID: https://orcid.org/0000-0002-3375-7726)
- Chiara Guidolin (ORCID: https://orcid.org/0000-0002-8682-2114)
- Chiara Lomazzi (ORCID: https://orcid.org/0000-0003-0172-1291)
- Andrea Disanza (ORCID: https://orcid.org/0000-0001-5101-2907)
- Sara Sigismund (ORCID: https://orcid.org/0000-0002-1396-4453)
- Alexandre Mironov (ORCID: https://orcid.org/0000-0002-3811-5802)
- Paolo Maiuri (ORCID: https://orcid.org/0000-0001-5079-445X)
- Andreas Schertel
- Andrea Francesco Benvenuto
- Alexander Cartagena-Rivera
- Diana A. van Faassen
- Elisabetta A. Cavalcanti-Adam
Institutions
- National Institutes of Health (US)
- Carl Zeiss (Germany) (DE)
- Radboud University Nijmegen (NL)
- University of Milan (IT)
- University of Trento (IT)
- Max Planck Institute for Medical Research (DE)
- National Institute of Biomedical Imaging and Bioengineering (US)
- Provincia Autonoma di Trento (IT)
- IFOM (IT)
- Human Technopole (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Institute of Biomedical Technologies (IT)
- University of Bayreuth (DE)
- European Institute of Oncology (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Nature Materials
- Published
- 2026-03-23
- DOI
- https://doi.org/10.1038/s41563-026-02553-2
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00