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Purpose <p>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.</p> Methods <p>A novel cell-stretch coupling device was developed by integrating tunable P(SBMA-co-AAm) hydrogels (8.9, 49.4, and 99.5&#xa0;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&#xa0;Hz). Inhibitors (PF228 for FAK, PP1 for Src, ML-7 for cytoskeleton) were used to dissect signaling pathways.</p> Results <p>On soft and medium-stiffness substrates (8.9–49.4&#xa0;kPa), cyclic stretching significantly enhanced cell migration (by 22.5–38.7%) and activated FAK/Src while suppressing RhoGDI α. High stiffness (99.5&#xa0;kPa) rendered cells unresponsive to stretch (≤&#xa0;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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Yii-Chun Chen,
  • Shuai Shao,
  • Xiaohui Yu,
  • Chao Guo,
  • Daqing Wang,
  • Hangyu Zhang,
  • Bo Liu

摘要

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.