Mechanical memory as a metastatic compass: a comparative framework for understanding organotropism through...

The seed and soil hypothesis has long explained organotropic metastasis through biochemical compatibility between tumor cells and distant tissues. However, accumulating evidence points to the role of mechanobiology in this process. This review proposes a framework in which cellular mechanical memory, the persistent adaptation to physical cues, functions as a mechanical compass that influences metastatic destination. We analyze how cancer cells, conditioned by the physical properties of the primary tumor (such as stiffness and viscosity), are epigenetically programmed to colonize distant organs with compatible mechanical signatures. We examine stiffness matching in bone metastasis, where cells conditioned by fibrotic tumors preferentially home to rigid skeletal niches, mediated by pathways including YAP/TAZ and RUNX2. We then address the paradox of soft tissue metastasis (brain, liver), proposing that a dual mechanical memory enables adaptation to compliant, viscoelastic environments. The role of dynamic forces, including fluid shear stress and cyclic strain, is examined in the context of lung colonization. By synthesizing these findings, we establish a comparative framework in which multidimensional mechanical memory, spanning static stiffness, viscoelasticity, and dynamic forces, contributes to organotropism as a complementary determinant alongside biochemical signaling. This framework generates testable predictions: that pharmacological disruption of specific mechanosensors or epigenetic erasure of stiffness memory should alter organ-specific metastatic patterns in preclinical models. Such a mechanobiological and biomechanical perspective may open therapeutic opportunities aimed at disrupting these physical memories to reduce metastatic dissemination.