Single-cell mechanics of cancer metastasis: A mechanical cascade perspective

Cancer metastasis remains the predominant driver of malignancy-related mortality, accounting for approximately 15% of annual deaths globally. While traditional oncological research focuses heavily on genetic and biochemical signaling networks, metastasis is fundamentally a physical process. To establish secondary lesions, tumor cells must leave the primary tumor mass, survive transport through the circulatory or lymphatic networks, adhere to distant vascular walls, and extravasate into target organs. Each stage of this metastatic cascade acts as a stringent mechanical filter, exerting severe physical selection pressures, such as fluid shear stress, compressive forces, and steric microenvironmental confinement, that eliminate vulnerable tumor cells. This review provides a comprehensive synthesis of single-cell and cell-cluster mechanics across the four critical stages of the hematogenous metastatic cascade: intravasation, circulation, arrest/adhesion, and extravasation. We detail how structural determinants, including nuclear lamina composition, LINC-mediated mucleoskeletal-cytoskeletal coupling, and integrin-mediated mechanotransduction, allow adaptive tumor cells to overcome physical barriers. Furthermore, we evaluate the biomechanical advantages of multicellular circulating tumor cell (CTC) clusters, exploring how heterotypic associations and extracellular matrix scaffolding enhance mechanical survival. By integrating quantitative parameters, such as permissive hemodynamic flow velocities (400–600 m/s) and receptor-ligand stabilization forces (80–200 pN), with molecular pathways (VEGFR2, YAP, TRPV4, and VE-cadherin), this review highlights mechanobiology as a crucial framework for predicting prognosis and identifying novel mechanotherapeutic vulnerabilities in advanced metastatic disease.