Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

Yuqi Zhang, Yizeng Li, Keyata N. Thompson, Konstantin Stoletov, Qinling Yuan, Kaustav Bera, Se Jong Lee, Runchen Zhao, Alexander Kiepas, Yao Wang, Panagiotis Mistriotis, Selma A. Serra, John D. Lewis, Miguel A. Valverde, Stuart S. Martin, Sean X. Sun () and Konstantinos Konstantopoulos ()
Additional contact information
Yuqi Zhang: The Johns Hopkins University
Yizeng Li: Binghamton University
Keyata N. Thompson: Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, University of Maryland School of Medicine
Konstantin Stoletov: University of Alberta
Qinling Yuan: The Johns Hopkins University
Kaustav Bera: The Johns Hopkins University
Se Jong Lee: The Johns Hopkins University
Runchen Zhao: The Johns Hopkins University
Alexander Kiepas: The Johns Hopkins University
Yao Wang: The Johns Hopkins University
Panagiotis Mistriotis: The Johns Hopkins University
Selma A. Serra: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra
John D. Lewis: University of Alberta
Miguel A. Valverde: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra
Stuart S. Martin: Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, University of Maryland School of Medicine
Sean X. Sun: The Johns Hopkins University
Konstantinos Konstantopoulos: The Johns Hopkins University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33683-1

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