Mechanisms of active wetting and fluidification in epithelial cell collectives
Year: 2026
Type: article
Abstract: Tissue-level phase transitions are emerging as a crucial mechanism in tumour development and metastasis. This study aims to identify molecular determinants and physical conditions that control active wetting and solid-to-fluid transition of epithelial tissues. We focused on IRSp53, a protein linking plasma membranes to the cytoskeleton. Depleting IRSp53, in MCF10 DCIS.com cells, disrupts coordinated collective movement by promoting local fluctuations in cell velocity resulting in increased tissue fluidity. In dense monolayers, IRSp53 ablation allows cells to escape the physical constraint imposed by cell crowding resulting in a delayed transition toward a jammed state. In 3D spheroids, IRSp53 loss fosters active wetting of a rigid substrate, shifting spheroid behaviour to a more fluid-like state. Biophysical modelling of the spreading cells as an active polar fluid indicates that IRSp53 depletion reduces bulk viscosity and contractility in spheroids. This effect is the result of reduced supracellular tension and disrupted organization of cell-cell junctions, which lead to decreased intercellular friction and enhanced local cell rearrangements. Molecularly, IRSp53 physically and functionally interacts with the junctional protein Afadin in the regulation of tissue tensile state and active wetting in tumour spheroids. These findings identify IRSp53 and Afadin as key regulators of tissue viscosity in breast cancer tumoroid undergoing solid-to-fluid transition linked to tumour progression. They further provide the molecular basis to causally relate subcellular and cell scale processes to tissue-levels dynamics.
Source: Nature Materials
Authors: Stefano Marchesi, Chiara Guidolin, Andrew E. Massey, Gregoire Lemahieu, Zeno Lavagnino, Galina V. Beznoussenko, Alexandre A. Mironov, Brenda J. Green, Elisa Allievi, Emanuele Martini, Serena Magni, Andrea Ghisleni, Caterina Lomazzi, Andrea Francesco Benvenuto, Andreas Schertel, Diana A. van Faassen, Stefano Freddi, Giovanni Bertalot, Dario Parazzoli, Paolo Maiuri, Marina Mapelli, Salvatore Pece, Sara Sigismund, Nils C. Gauthier, Elisabetta A. Cavalcanti-Adam, Alexander X. Cartagena-Rivera, Fabio Giavazzi, Giorgio Scita, Andrea Disanza
Institutions: IFOM, University of Milan, National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering, Max Planck Institute for Medical Research, Human Technopole, European Institute of Oncology, Carl Zeiss (Germany), Radboud University Nijmegen, University of Trento, University of Naples Federico II, University of Bayreuth
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funder: National Institutes of Health
Award: Mechanobiology
OpenAlex ID: W7140130087