The Synergistic Regulation of Lung Cancer Cell Migration by Tensile Stress and Matrix Stiffness

To investigate the synergistic effects of matrix stiffness and cyclic tensile stress-key mechanical cues in the lung tumor microenvironment-on lung cancer cell migration, and to elucidate the underlying mechanotransduction pathways.

A novel cell-stretch coupling device was developed by integrating tunable P(SBMA-co-AAm) hydrogels (8.9, 49.4, and 99.5 kPa) with stretchable PDMS chambers via an interpenetrating polymer network. A549 lung cancer cells expressing FRET-based biosensors for FAK, Src, and RhoGDI α were subjected to cyclic stretching (10 or 20% strain, 1 Hz). Inhibitors (PF228 for FAK, PP1 for Src, ML-7 for cytoskeleton) were used to dissect signaling pathways.

On soft and medium-stiffness substrates (8.9-49.4 kPa), cyclic stretching significantly enhanced cell migration (by 22.5-38.7%) and activated FAK/Src while suppressing RhoGDI α. High stiffness (99.5 kPa) rendered cells unresponsive to stretch (≤ 3.2% change). FAK and Src jointly regulated RhoGDI α, with FAK dominance under low stiffness. Cytoskeletal inhibition abolished mechanoresponses, confirming its role as a central mechanosensor.

The study establishes a biomimetic platform for dual mechanical stimulation and reveals stiffness-dependent synergy between tensile stress and matrix stiffness in promoting lung cancer migration via the FAK/Src-RhoGDI α axis. These findings provide mechanistic insights into mechanotransduction in lung cancer and suggest potential targets for inhibiting metastasis by disrupting mechanical signaling.

The online version contains supplementary material available at 10.1007/s12195-026-00914-0.