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; Konstantinos Konstantopoulos

doi:10.1038/s41467-022-33683-1

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.

Authors

Yuqi Zhang^{1

2}, Yizeng Li³, Keyata N Thompson⁴, Konstantin Stoletov⁵, Qinling Yuan^{1

2}, Kaustav Bera^{1

2}, Se Jong Lee^{1

2}, Runchen Zhao^{1

2}, Alexander Kiepas^{1

2}, Yao Wang^{1

2}, Panagiotis Mistriotis^{1

2

6}, Selma A Serra⁷, John D Lewis⁵, Miguel A Valverde⁷, Stuart S Martin^{4

8}, Sean X Sun^{9

10

11

12}, Konstantinos Konstantopoulos^{13

14

15

16}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA.
² Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA.
³ Department of Biomedical Engineering, Binghamton University, SUNY, Binghamton, NY, 13902, USA.
⁴ Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁵ Department of Oncology, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
⁶ Department of Chemical Engineering, Auburn University, Auburn, AL, 36849, USA.
⁷ Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.
⁸ Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. ssun@jhu.edu.
¹⁰ Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA. ssun@jhu.edu.
¹¹ Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. ssun@jhu.edu.
¹² Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. ssun@jhu.edu.
¹³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. konstant@jhu.edu.
¹⁴ Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA. konstant@jhu.edu.
¹⁵ Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. konstant@jhu.edu.
¹⁶ Department of Oncology, The Johns Hopkins University, Baltimore, MD, 21205, USA. konstant@jhu.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Movement / physiology
Cell Size
Humans
Neoplasms*
Sodium-Hydrogen Exchangers*
Water

Substances

Sodium-Hydrogen Exchangers
Water

Abstract

Publication types

MeSH terms

Substances

Grants and funding