Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

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• dc.contributor.author Zhang, Yuqi
• dc.contributor.author Li, Yizeng
• dc.contributor.author Thompson, Keyata N.
• dc.contributor.author Stoletov, Konstantin
• dc.contributor.author Yuan, Qinling
• dc.contributor.author Bera, Kaustav
• dc.contributor.author Lee, Se Jong
• dc.contributor.author Zhao, Runchen
• dc.contributor.author Kiepas, Alexander
• dc.contributor.author Wang, Yao
• dc.contributor.author Mistriotis, Panagiotis
• dc.contributor.author Serra, Selma A.
• dc.contributor.author Lewis, John D.
• dc.contributor.author Valverde, M. A. (Miguel Ángel), 1963-
• dc.contributor.author Martin, Stuart S.
• dc.contributor.author Sun, Sean X.
• dc.contributor.author Konstantopoulos, Konstantinos
• dc.date.accessioned 2022-11-17T07:01:37Z
• dc.date.available 2022-11-17T07:01:37Z
• dc.date.issued 2022
• dc.description.abstract Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. According to the Osmotic Engine Model, polarization of NHE1 at the leading edge of confined cells facilitates water uptake, cell protrusion and motility. The physiological relevance of the Osmotic Engine Model and the identity of molecules mediating cell rear shrinkage remain elusive. Here, we demonstrate that NHE1 and SWELL1 preferentially polarize at the cell leading and trailing edges, respectively, mediate cell volume regulation, cell dissemination from spheroids and confined migration. SWELL1 polarization confers migration direction and efficiency, as predicted mathematically and determined experimentally via optogenetic spatiotemporal regulation. Optogenetic RhoA activation at the cell front triggers SWELL1 re-distribution and migration direction reversal in SWELL1-expressing, but not SWELL1-knockdown, cells. Efficient cell reversal also requires Cdc42, which controls NHE1 repolarization. Dual NHE1/SWELL1 knockdown inhibits breast cancer cell extravasation and metastasis in vivo, thereby illustrating the physiological significance of the Osmotic Engine Model.
• dc.description.sponsorship This work was supported, in part, by an NIH/NCI R01 CA254193 (K.K., S.S.M., and S.X.S.), R01 GM134542 (S.X.S. and K.K.), NSF 2045715 (Y.L.), the Spanish Ministry of Science, Education and Universities through grants RTI2018-099718-B-100 (M.A.V.), an institutional “Maria de Maeztu” Programme for Units of Excellence in R&D and FEDER funds (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 (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.identifier.citation Zhang Y, Li Y, Thompson KN, Stoletov K, Yuan Q, Bera K, Lee SJ, Zhao R, Kiepas A, Wang Y, Mistriotis P, Serra SA, Lewis JD, Valverde MA, Martin SS, Sun SX, Konstantopoulos K. Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis. Nat Commun. 2022 Oct 17;13(1):6128. DOI: 10.1038/s41467-022-33683-1
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-33683-1
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/54901
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2022 Oct 17;13(1):6128
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099718-B-100
• 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Breast cancer
• dc.subject.keyword Cell invasion
• dc.subject.keyword Cell polarity
• dc.subject.keyword Metastasis
• dc.title Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion