Locked Nucleic Acid-Modified Force Probe Reveals High-Force Regulation of Yes-Associated Protein through Talin-Vinculin in Breast Cancer.

Abstract

Integrins facilitate cellular mechanotransduction by transmitting mechanical cues from the extracellular matrix. While various DNA-based force probes have demonstrated integrin tension-dependent cellular responses, these typically measure forces up to ∼56 pN, limiting investigations of higher-force mechanobiological responses. Here, we develop a locked nucleic acid-based tension gauge tether (LNA-TGT) capable of measuring higher integrin tensions with increased stability compared to traditional DNA-based sensors. The LNA-TGT reveals that metastatic breast cancer cells exhibit a marked reduction in yes-associated protein (YAP) nuclear translocation under high-force conditions (approximately 60 pN). This effect correlates with a biphasic interaction between talin and vinculin at focal adhesions (FAs), which weakens at elevated tensions. Consequently, this leads to FA disassembly, actin fiber disruption, and diminished mechanical signaling to the nucleus. These findings suggest that LNA-TGTs provide a robust platform to probe high-force mechanotransduction, advancing our understanding of the relationship between integrin tension, cytoskeletal dynamics, and nuclear signaling in cells.