Nesprin-2-mediated epigenetic remodeling under mechanical load: anti-tumor mechanisms and strategies

Primary tumors of the heart are rare, and metastatic growth within the heart is typically limited. In this study previously published in Science, the authors used genetically engineered cancer models, heterotopic heart transplantation, and engineered heart tissue systems to demonstrate that mechanical load directly contributes to the suppression of malignancy. Remarkably, removal of this mechanical load alone was sufficient to permit tumor growth in the heart. At the molecular level, cardiac mechanical load induced a shared epigenetic landscape in metastatic cells, characterized by loss of H3K9me3, increased chromatin accessibility, and activation of growth-suppressive transcriptional programs. Functional screening identified Nesprin-2, a core component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, as a critical mediator of this process. Given that Nesprin-2 itself is unlikely to be directly druggable, targeting downstream epigenetic pathways or therapeutically mimicking mechanical load may represent promising anticancer strategies.