Matrix stiffness encoded mechanical memory maintains proliferative dominance in tumor metastasis

Clinical observations revealed that the progression of newly developed pulmonary metastasis during systemic therapy reflected resistance in primary lesions and suggested that metastatic foci may retain biological characteristics similar to those of the primary tumor. However, how tumor cells in pulmonary metastatic lesions retained the biological characteristics of the primary tumor in different microenvironments remained unclear. We reported that mechanical memory enabled tumor cells to resist biomechanical stress and sustain malignant traits. Stiff matrix activated the RhoA-ROCK1 signaling pathway, leading to actin cytoskeletal remodeling and the suppression of mitochondrial fission. This dysregulation of mitochondrial dynamics enhanced fatty acid beta-oxidation, accumulating acetyl-CoA and subsequent histone hyperacetylation. This epigenetic reprogramming was mitotically heritable, allowing progeny cells to retain a proliferative advantage after detachment from stiff environments. Inhibiting RhoA-ROCK1 disrupted mechanical memory, reducing HCC pulmonary metastasis. Our findings proposed targeting mechanical memory as a novel metastasis prevention strategy.