Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

• DOI: 10.1038/s41467-022-33683-1
• Publication Date: 2022-10-17T12:08:14Z
• Authors: Yuqi Zhang; Yizeng Li; Keyata N. Thompson; Konstantin Stoletov; Qinling Yuan; Kaustav Bera; Se Jong Lee; Runchen Zhao; Alexander Kiepas; Yao Wang; Panagiotis Mistri...; Selma A. Serra; John D. Lewis; Miguel A. Valverde; Stuart S. Martin; Sean X. Sun; Konstantinos Kons...
• Keywords: Cell polarity; CDC42

Abstract Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. According to the Osmotic Engine Model, polarization of NHE1 at leading edge confined cells facilitates water uptake, cell protrusion and motility. The physiological relevance Model identity molecules mediating rear shrinkage remain elusive. Here, we demonstrate that SWELL1 preferentially polarize trailing edges, respectively, mediate volume regulation, dissemination from spheroids migration. confers direction efficiency, as predicted mathematically determined experimentally via optogenetic spatiotemporal regulation. Optogenetic RhoA activation front triggers re-distribution reversal in SWELL1-expressing, but not SWELL1-knockdown, cells. Efficient also requires Cdc42, which controls repolarization. Dual NHE1/SWELL1 knockdown inhibits breast extravasation metastasis vivo, thereby illustrating significance Model.