A1 Refereed original research article in a scientific journal
RAB5A Promotes Active Fluid Wetting by Reprogramming Breast Cancer Spheroid Mechanics
Authors: Lemahieu, Gregoire; Moreno-Layseca, Paulina; Hub, Tobias; Bevilacqua, Carlo; Gomez-Gonzalez, Manuel; Pennarola, Federica; Colombo, Federico; Massey, Andrew E.; Barzaghi, Leonardo; Palamidessi, Andrea; Homagk, Leon-Luca; Barnett, Samuel F. H.; Cartagena-Rivera, Alexander X.; Selhuber-Unkel, Christine; Prevedel, Robert; Trepat, Xavier; Spatz, Joachim P.; Ivaska, Johanna; Scita, Giorgio; Cavalcanti-Adam, Elisabetta Ada
Publisher: Wiley
Publishing place: HOBOKEN
Publication year: 2025
Journal: Advanced Science
Journal name in source: Advanced Science
Journal acronym: ADV SCI
Article number: e03569
Number of pages: 18
ISSN: 2198-3844
eISSN: 2198-3844
DOI: https://doi.org/10.1002/advs.202503569
Web address : https://doi.org/10.1002/advs.202503569
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/499589471
Unjamming transitions from a solid-like to a fluid-like state are a gateway to breast epithelial cancer invasion. However, the mechanical interplay between phase transitions and dimension transitions, in particular wetting, remains elusive, despite being critical for understanding the onset of metastatic dissemination. This study shows that unjamming, mediated by the RAB5A GTPase, alters carcinoma spheroid fluidity, rigidity, and rewires adhesion mechanics to drive supracellular active wetting as a new mode of tumor expansion. Spheroid fluidification enhances the selective expression of integrin subunits and increases focal adhesion dynamics, inducing a fluid-like spreading behavior on specific matrix ligands. Notably, nanoscale regulation of integrin clustering can select for distinct phase transitions at the collective scale upon wetting. In this framework, fluidized spheroids polarize into cohesive "supracells", and maintain a stiff peripheral actin bundle as measured by nanomechanical mapping. Furthermore, a combination of Brillouin microscopy and 2.5D traction force analysis reveals a mechanical switch within the spheroid core, characterized by significant cell softening and a reduction in compressive forces exerted on the substrate, thereby mimicking the wetting of a liquid droplet. These findings establish unjamming-driven active wetting as a key mechanism to comprehend the molecular and biophysical underpinnings of solid tumor invasion.
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The authors thank the members of the labs from E.A.C.-A. and G.S. for help, scientific discussions, trainings. In particular, the authors thank J. Bauer and F. Noureddine for their support, scientific input at the early steps of the project; J. Grigoridis for his help in performing SEM on nanopatterned substrates; J. Siivonen for technical assistance; F. Giavazzi for his general input in the project; A. Disanza for proofreading the manuscript; L. Wang and M. Piel for the TFM protocol, for sharing soft PDMS material; F. Sessler, the Soft (bio) Materials Characterization Core Facility (Biomechanics) at IMSEAM (Heidelberg University) for providing professional service, nanoindentation instrumentation; the Cell Imaging, Cytometry Core, the Genome Editing core (Turku Bioscience, University of Turku, abo Akademi University, Biocenter Finland), for providing professional services, instrumentation, expertise; the Euro-Bioimaging ((www.eurobioimaging.eu) for providing access to imaging technologies, services via the Finnish Advanced Light Microscopy Node (Turku, Finland). The authors acknowledge general support from the Max Planck Society. E.A.C.-A., C.S.-U., and J.P.S. acknowledge funding through the Max Planck School Matter to Life supported by the German Federal Ministry of Education, Research (BMBF). E.A.C.-A. was supported by the Bavarian High-Tech Agenda Program. This work was supported by the Finnish Cancer Institute (K. Albin Johansson Professorship, J.I.); a Research Council of Finland project grant (# 325464 to J.I.), Centre of Excellence program (# 346131, J.I.); the Cancer Foundation Finland (J.I.); the Sigrid Juselius Foundation (J.I.); the Research Council of Finland's Flagship InFLAMES (# 337530 and 357910), the Jane, Aatos Erkko Foundation (J.I.). P.M.-L. was supported by the Research Council of Finland postdoctoral fellowship (grant No. 321493). R.P. acknowledges support of an european research council (ERC) Consolidator Grant (no. 864027, Brillouin4Life), the German Center for Lung Research (DZL). The work of C.B. and R.P. was supported by funds from the European Molecular Biology Laboratory. The work of M.G.-G. and X.T. was supported by the Generalitat de Catalunya (AGAUR SGR-2017-01602), the Spanish Ministry for Science, Innovation MICCINN/FEDER (PID2021-128635NB-I00, MCIN/AEI/10.13039/501100011033, "ERDF-EU A way of making Europe"), European Research Council (Adv-883739 to X.T.), La Caixa Foundation (LCF/PR/HR20/52400004). IBEC is recipient of a Severo Ochoa Award of Excellence from ministry of economy and competitiveness (MINECO). C.S.-U. and F.C. thank the ERC for support through the Consolidator Grant PHOTOMECH (Grant No. 101001797), the Volkswagen Foundation through the Initiative "Life?", Az. 96733, the German Research Foundation via the Excellence Cluster 3D Matter Made to Order (EXC-2082/1-390761711). A.X.C.-R. and A.E.M. acknowledge support by the intramural funding of the Division of Intramural Research Program at the National Institutes of Biomedical Imaging, Bioengineering with grant #ZIA-EB000094, the National Institutes of Health central funds for the national institutes of health (NIH) Distinguished Scholars Program award.Open access funding enabled and organized by Projekt DEAL
