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Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

Author

Listed:
  • Yuqi Zhang

    (The Johns Hopkins University
    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
    The Johns Hopkins University)

  • Kaustav Bera

    (The Johns Hopkins University
    The Johns Hopkins University)

  • Se Jong Lee

    (The Johns Hopkins University
    The Johns Hopkins University)

  • Runchen Zhao

    (The Johns Hopkins University
    The Johns Hopkins University)

  • Alexander Kiepas

    (The Johns Hopkins University
    The Johns Hopkins University)

  • Yao Wang

    (The Johns Hopkins University
    The Johns Hopkins University)

  • Panagiotis Mistriotis

    (The Johns Hopkins University
    The Johns Hopkins University
    Auburn 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
    University of Maryland School of Medicine)

  • Sean X. Sun

    (The Johns Hopkins University
    The Johns Hopkins University
    The Johns Hopkins University
    The Johns Hopkins University)

  • Konstantinos Konstantopoulos

    (The Johns Hopkins University
    The Johns Hopkins University
    The Johns Hopkins University
    The Johns Hopkins University)

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.

Suggested Citation

  • 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 & Jo, 2022. "Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33683-1
    DOI: 10.1038/s41467-022-33683-1
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    References listed on IDEAS

    as
    1. Léo Valon & Ariadna Marín-Llauradó & Thomas Wyatt & Guillaume Charras & Xavier Trepat, 2017. "Optogenetic control of cellular forces and mechanotransduction," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
    2. Wen Deng & Jack A. Bates & Hai Wei & Michael D. Bartoschek & Barbara Conradt & Heinrich Leonhardt, 2020. "Tunable light and drug induced depletion of target proteins," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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