Mechanoadaptation via Myosin Cytoplasmic Redistribution Protects Circulating Tumor Cells From Shear‐induced Death During Hematogenous Dissemination

ABSTRACT To initiate distant metastasis via hematogenous dissemination, circulating tumor cells (CTCs) must survive shear‐induced destruction in vasculature. However, how CTCs withstand such mechanical interrogation remains poorly understood. Using both patient‐derived primary cells and cancer cell lines, this study reports that non‐adherent tumor cells mechanically adapt to increasing fluid shear stress (FSS) through re‐distribution of activated myosin into cytoplasm. Cytoplasmic but not cortical myosin attenuates force transmission from cell surface into chromatin by disrupting the binding of myosin with actin, which is recapitulated by a cytoskeletal fluidization‐based model. Under high FSS, Lamin A/C‐mediated nuclear mechanosensing elevates nuclear envelop tension and triggers calcium release from endoplasmic reticulum, which redistributes myosin into cytoplasm through Rho‐associated protein kinase. Targeting cytoplasmic myosin‐mediated mechanoadaptation restores mechanoresponses and re‐sensitizes CTCs to shear‐induced death, which eventually reduces tumor metastasis. In summary, these results unveil the reduction of force transmission of CTCs in response to harsh shearing via cytoplasmic myosin accumulation, which potentiates mechanoadaptation and protects them from shear‐induced apoptosis during hematogenous metastasis.