Year: 2026
Type: preprint
Abstract: Confined migration is essential for metastasis, yet how cells adapt their migratory and metabolic programs across stiffness-varying microenvironments remains unclear. We uncover a stiffness-dependent mechano-metabolic switch governing migration. In stiff microchannels, cells utilize the osmotic engine model (OEM), relying on NHE1 activity, front-polarization, and glycolysis. In soft microchannels, migration is OEM-independent and requires pyruvate-fueled oxidative phosphorylation (OxPHOS). This OxPHOS-driven motility depends on Arp3, β1-integrin and integrin-linked kinase, which increase membrane tension in confinement that in turn triggers TRPM7-mediated calcium influx and RhoA-/myosin-II contractility. Activating and polarizing NHE1, via overexpression, hypoxia or elevated viscosity, restore OEM- and glycolysis-dependent migration in soft microchannels, bypassing the need for actin polymerization in vitro and in chick embryos. Mitochondria addition reinstates Arp3 polarization and enhances migration in NHE1-overexpressing cells, enabling engagement of both mechanisms in vitro and in zebrafish. These findings uncover a previously unrecognized mechano-metabolic link, revealing that intracellular rewiring overrides stiffness-dependent metabolic demands.
Authors: Alice Amitrano, Debanik Choudhury, Brent Ifemembi, Alexandros Afthinos, Konstantin Stoletov, Qinling Yuan, Sanjiban Nath, Bishwa Ranjan Si, Bhawana Agarwal, Gianna Graziano, Jack Gao, Anneliese Ceisel, Matthew Hauf, Sean X. Sun, Andrew J. Ewald, Miguel A. Valverde, John D. Lewis, Jeff Mumm, Konstantinos Konstantopoulos
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204122605