Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

Area of Science:

• Cell Biology
• Biophysics
• Cancer Research

Background:

• Cell migration is crucial for physiological processes and cancer metastasis.
• The Osmotic Engine Model proposes NHE1 polarization drives cell motility in confined spaces.
• The model's in vivo relevance and rear-shrinkage mechanisms were previously unclear.

Purpose of the Study:

• To investigate the roles of NHE1 and SWELL1 in cell migration and volume regulation.
• To validate the physiological significance of the Osmotic Engine Model.
• To identify molecular mechanisms underlying cell rear shrinkage and migration reversal.

Main Methods:

• Utilized optogenetics for spatiotemporal control of protein localization and cell behavior.
• Employed spheroid dissemination and confined migration assays.
• Performed in vivo studies using dual NHE1/SWELL1 knockdown in breast cancer models.

Main Results:

• NHE1 and SWELL1 polarized at leading and trailing cell edges, respectively, mediating volume regulation and migration.
• SWELL1 polarization was essential for migration direction and efficiency, confirmed by mathematical modeling and optogenetics.
• Optogenetic RhoA activation induced SWELL1 redistribution and migration reversal, dependent on Cdc42 and NHE1 repolarization.
• Combined NHE1/SWELL1 knockdown significantly reduced breast cancer cell extravasation and metastasis in vivo.

Conclusions:

• The study validates the Osmotic Engine Model by demonstrating the roles of NHE1 and SWELL1 in cell migration and volume control.
• NHE1 and SWELL1 polarization are key regulators of cell dissemination and confined migration.
• Targeting NHE1 and SWELL1 offers a potential therapeutic strategy against cancer metastasis.