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Extracellular fluid viscosity enhances cell migration and cancer dissemination

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dc.contributor.author Bera, Kaustav
dc.contributor.author Serra, Selma A.
dc.contributor.author Valverde, M. A. (Miguel Ángel), 1963-
dc.contributor.author Konstantopoulos, Konstantinos
dc.date.accessioned 2022-11-10T06:50:26Z
dc.date.available 2022-11-10T06:50:26Z
dc.date.issued 2022
dc.identifier.citation Bera K, Kiepas A, Godet I, Li Y, Mehta P, Ifemembi B et al. Extracellular fluid viscosity enhances cell migration and cancer dissemination. Nature. 2022 Nov 2. DOI: 10.1038/s41586-022-05394-6
dc.identifier.issn 0028-0836
dc.identifier.uri http://hdl.handle.net/10230/54780
dc.description Data de publicació electrònica: 02-11-2022
dc.description.abstract Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.
dc.description.sponsorship This work was supported in part by R01 CA257647 (to K.K. and D.M.G.), R01 GM134542 (to S.X.S. and K.K.), NSF 2045715 (to Y.L.), R01 AR071976 (to C.-M.F. and J.T.), R01 AR072644 (to C.-M.F. and J.T.) and R01 CA054358 (to A.P.F.), the Spanish Ministry of Science, Education and Universities through grants RTI2018 099718-B-100 (to M.A.V.) and an institutional “Maria de Maeztu” Programme for Units of Excellence in R&D and FEDER funds (to M.A.V.), and postdoctoral fellowships from the Fonds de recherche du Quebec—Nature et technologies and the Natural Sciences and Engineering Research Council of Canada (to A.K.). The opinions, findings and conclusions, or recommendations expressed are those of the authors and do not necessarily reflect the views of any of the funding agencies.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nature. 2022 Nov 2
dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Extracellular fluid viscosity enhances cell migration and cancer dissemination
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41586-022-05394-6
dc.subject.keyword Cancer microenvironment
dc.subject.keyword Cell migration
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099718-B-100
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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