Mechanochemical cues control the coupling of metabolic and migratory patterns in cancer

The study reveals a crucial link between mechanical cues and the metabolic and migratory patterns of cancer cells. In confined environments, cancer cells employ a mechano-metabolic switch to adapt their movement and energy consumption based on the stiffness of their surroundings. In stiff conditions, cells utilize the osmotic engine model (OEM), which relies on the activity of NHE1, front-polarization, and glycolysis to migrate.

In softer conditions, however, migration occurs independently of OEM, instead relying on oxidative phosphorylation (OxPHOS) fueled by pyruvate. This OxPHOS-driven motility is facilitated by Arp3, β1-integrin, and integrin-linked kinase, which increase membrane tension in confined spaces. This tension triggers TRPM7-mediated calcium influx and RhoA-/myosin-II contractility, enabling cell movement.

Interestingly, the study finds that artificially activating and polarizing NHE1, through methods like overexpression, hypoxia, or elevated viscosity, can restore OEM-dependent migration in soft environments without relying on actin polymerization. Additionally, adding mitochondria to NHE1-overexpressing cells enhances migration and reinstates Arp3 polarization, demonstrating that both metabolic pathways can be engaged simultaneously in vitro and in zebrafish embryos.

This discovery highlights an unexpected mechanistic connection, showing how cells can rewire their internal processes to override the metabolic demands imposed by stiffness.