TRPM7 Annexin A1 Mechanosensitive Pathway Drives Capillary Infiltration by Circulating Tumor Cells

Successful metastatic dissemination requires tumor cells to overcome significant physical barriers. When circulating tumor cells (CTCs) become lodged in capillary beds, studies reveal that only a small subset can adapt to fluid shear stress (FSS) within the constricted vasculature. These rare, mechanically resilient cells may subsequently extravasate and form metastatic lesions, but details on this adaptation of the physical environment and its molecular basis are not well understood. Utilizing a microfluidics platform that mimics microcirculatory dynamics, we discover that only breast cancer cells with high metastatic potential maintain directional migration under physiologically relevant FSS conditions. This highlights the mechanical selection process of metastatic precursors during hematogenous dissemination. We identify the TRPM7-Annexin A1-actin signaling pathway as essential for overcoming physical barriers and regulating cell motility under capillary FSS. FSS prompts cytoskeletal reorganization and actin disassembly, restricting cell movement. Cancer cells respond to this by increasing mechanical loading, activating TRPM7 and triggering calcium influx, which then activates Annexin A1. This calcium-dependent protein, Annexin A1, interacts with the actin cortex to prevent FSS-induced actin disassembly, thus aiding migration. Experiments conducted in mouse liver capillaries validate the critical role of this pathway in cancer cell motility. Additionally, we propose a mechano-pharmacological strategy using FTY720 to target the TRPM7 pathway, highlighting its therapeutic potential to modify CTC receptor specificity and inhibit distant metastasis.