Zhang, YuqiLi, YizengThompson, Keyata N.Stoletov, KonstantinYuan, QinlingBera, KaustavLee, Se JongZhao, RunchenKiepas, AlexanderWang, YaoMistriotis, PanagiotisSerra, Selma A.Lewis, John D.Valverde, M. A. (Miguel Ángel), 1963-Martin, Stuart S.Sun, Sean X.Konstantopoulos, Konstantinos2022-11-172022-11-172022Zhang 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/s41467-022-33683-12041-1723http://hdl.handle.net/10230/54901Cell 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-022-33683-1Breast cancerCell invasionCell polarityMetastasisinfo:eu-repo/semantics/openAccess