Matrix Stiffness–Encoded Mechanical Memory Maintains Proliferative Dominance in Metastatic Tumors

Abstract Primary and metastatic lesions share similar biological properties despite existing in different microenvironments. A better understanding of the mechanisms underlying the maintenance of phenotypic homogeneity in heterogeneous microenvironments could help identify strategies for suppressing metastasis. In this study, we found that mechanical memory enabled tumor cells to resist biomechanical stress and sustain malignant traits. Matrix stiffness activated the RhoA–ROCK1 signaling pathway, leading to actin cytoskeletal remodeling and suppression of mitochondrial fission. The dysregulation of mitochondrial dynamics enhanced fatty acid β-oxidation, leading to the accumulation of acetyl coenzyme A and subsequent histone hyperacetylation. The stiffness-mediated epigenetic reprogramming was mitotically heritable, allowing progeny cells to retain a proliferative advantage after detachment from stiff environments. Inhibition of RhoA–ROCK1 disrupted mechanical memory, thereby reducing metastasis. These findings suggest that targeting mechanical memory may be a strategy for preventing metastasis. Significance: Matrix stiffness induces metabolic and epigenetic rewiring that creates a lasting memory in cancer cells that supports metastasis, revealing mechanical memory as a potential target for metastasis prevention. See related article by Kilian, p. XX .