Mechanical Stress Induces Nuclear Envelope Rupture in Melanoma Cells to Reorganize Tumor–Stromal Interactions

Abstract

Growth-induced solid stress and fluid pressure contribute to tumor progression and drug resistance. Beyond tumor endogenous physical forces, cells in the tumor microenvironment may also experience external macroscopic mechanical stress, and some tumors preferentially develop in weight-bearing regions with higher focal pressure. Characterization of the impact of macroscopic mechanical stress on the tumor microenvironment could help uncover the mechanistic links between external mechanical forces and increased tumor incidence. Here, we showed that recurrent macroscopic mechanical stress disrupts nuclear envelope integrity, leading to spatial reorganization and fibroblast subtype changes at the tumor–stromal interface. In mouse models of plantar melanoma, exogenous mechanical stress induced nuclear envelope rupture in melanoma cells and increased LRRC15-positive myofibroblasts. Reduction of nuclear envelope integrity through inducible deletion of Lmna likewise increased LRRC15-positive myofibroblast generation. Co-culture with myofibroblasts promoted nuclear envelope rupture in melanoma cells in 3D culture, suggesting a positive feedback loop. In addition, mechanical stress-driven transcriptomic changes in tumor and stromal cells were observed alongside enhanced lymph node metastasis and immunotherapy resistance. Analysis of human melanoma samples revealed mechanical stress-associated stromal remodeling and a higher incidence of lymph node metastasis in tumors arising in mechanically stressed regions, although these features were not significantly associated with overall survival. Together, these findings suggest that macroscopic mechanical stress may influence cancer progression by inducing nuclear envelope damage and reshaping tumor–stromal interactions.