High-Throughput Force Arrays Reveal Spatial Force Distribution as a Biomarker for Cancer Cell Identification and Drug Resistance Detection

Cellular traction force measurement has been used in numerous studies to understand cancer cell migration, invasion, and metastasis. However, due to limitations of the experimental designs, its application has a severe limit in high throughput real-time measurements. We present a cellular force detection system using a Force Arrays Screening Tool (FAST) for large-area cellar force measurement. FAST offers several advantages over current traction force detection systems, including label-free, real-time monitoring, and high throughput. FAST is a high-throughput traction force imaging platform capable of measuring traction force distributions across thousands of cells within seconds with single-cell resolution. We demonstrated that traction force distribution could be used as a powerful biophysical biomarker to access the cytotoxicity and distinguish cell types, as well as drug resistance. We have shown that drug-resistant and drug-sensitive lung cancer cells exhibited distinct spatial distribution of traction force. When the spatial distribution of traction force was used as a novel biomarker to identify drug-resistant cells, the changes in the traction force could be correlated to protein expression. We observed that changes in traction force correlated with YAP and β1-integrin, two key molecules known to mediate mechanical signaling. These molecules could be correlated with the spatial distribution of traction force and contributed to the resistance of lung cancer cells to the tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR). Inhibiting YAP or β1-integrin in the drug-resistant cancer cells converted not only mechanical phenotype but also drug sensitivity property into those of the drug-sensitive cancer cells. FAST enables single-cell resolution mapping of traction forces for more than 100,000 cells within one minute, fulfilling the gap in current traction force applications and revealing novel biomechanical signatures of cellular phenotypes with applications in disease diagnostics and drug discovery.