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

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

Biomedical Engineering

Binghamton University

Johns Hopkins University
University of Maryland Baltimore
University of Alberta
Auburn University
Pompeu Fabra University
University of Maryland, Baltimore

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English
Article number	6128
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33683-1
State	Published - Dec 2022

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Zhang, Y., Li, Y., Thompson, K. N., Stoletov, K., Yuan, Q., Bera, K., Lee, S. J., Zhao, R., Kiepas, A., Wang, Y., Mistriotis, P., Serra, S. A., Lewis, J. D., Valverde, M. A., Martin, S. S., Sun, S. X., & Konstantopoulos, K. (2022). Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis. Nature Communications, 13(1), Article 6128. https://doi.org/10.1038/s41467-022-33683-1

@article{f36743c4835c439d8a92930db1ec096f,

title = "Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33683-1",

language = "English",

volume = "13",

journal = "Nature Communications",

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Zhang, 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 2022, 'Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis', Nature Communications, vol. 13, no. 1, 6128. https://doi.org/10.1038/s41467-022-33683-1

TY - JOUR

T1 - Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

AU - Zhang, Yuqi

AU - Li, Yizeng

AU - Thompson, Keyata N.

AU - Stoletov, Konstantin

AU - Yuan, Qinling

AU - Bera, Kaustav

AU - Lee, Se Jong

AU - Zhao, Runchen

AU - Kiepas, Alexander

AU - Wang, Yao

AU - Mistriotis, Panagiotis

AU - Serra, Selma A.

AU - Lewis, John D.

AU - Valverde, Miguel A.

AU - Martin, Stuart S.

AU - Sun, Sean X.

AU - Konstantopoulos, Konstantinos

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85140011853

U2 - 10.1038/s41467-022-33683-1

DO - 10.1038/s41467-022-33683-1

M3 - Article

C2 - 36253369

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6128

ER -

Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

Abstract

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