Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis.

Alexander Kiepas, Konstantinos Konstantopoulos, Sean X Sun, Stuart S Martin, Miguel A Valverde, John D Lewis, Selma A Serra, Panagiotis Mistriotis, Yao Wang, Yuqi Zhang, Runchen Zhao, Se Jong Lee, Kaustav Bera, Qinling Yuan, Konstantin Stoletov, Keyata N Thompson, Yizeng Li

Journal: Nature communications 2022;13(1):6128

PMID: 36253369

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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.

Address: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA.; Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA.; Department of Biomedical Engineering, Binghamton University, SUNY, Binghamton, NY, 13902, USA.; Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.; Department of Oncology, University of Alberta, Edmonton, AB, T6G 2E1, Canada.; Department of Chemical Engineering, Auburn University, Auburn, AL, 36849, USA.; Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. [email protected].; Department of Oncology, The Johns Hopkins University, Baltimore, MD, 21205, USA. [email protected].

DOI: 10.1038/s41467-022-33683-1