Mechanical load inhibits cancer growth in mouse and human hearts.

The heart rarely develops cancer, and, at the same time, it lacks regenerative capacity, as cardiomyocytes stop proliferating after birth. This suggests that mechanisms limiting cardiac regeneration may also protect against cancer. In this work, we investigated the role of mechanical load and used in vivo cancer models and ex vivo engineered heart tissues to show that mechanical load reduces cancer cell proliferation in the myocardium. Spatial transcriptomics of human cardiac metastases revealed decreased histone methylation and chromatin compaction. These changes affect chromatin accessibility at proliferation-related loci, with Nesprin-2 identified as a key mechanosensor. Our results uncover how mechanical forces protect the heart from cancer and suggest potential strategies for cancer therapy based on mechanical stimulation. Editor's summary: It is very rare for cancer to either form in or metastasize to the heart, suggesting that there is something that inhibits cancer growth in the cardiac microenvironment. A key potential explanation is mechanical load. Ciucci et al. tested this idea by introducing cancer cells into rodent hearts and then in vitro engineering cardiac models with or without normal mechanical load. They also compared human tissue samples from rare cardiac metastases and corresponding extracardiac tumors. The authors determined that increased mechanical load promoted Nesprin-2 signaling, which then led to changes in chromatin compaction and histone methylation, resulting in the suppression of cancer growth (see the Perspective by Paltzer and Martin). —Yevgeniya Nusinovich INTRODUCTION: The heart is rarely affected by cancer; both primary cardiac tumors and metastases are uncommon despite the high vascularization of the myocardium. The mechanisms underlying this resistance remain unclear. RATIONALE: Mechanical load has been proposed as a major mechanism halting cardiomyocyte proliferation early after birth, thus limiting the regenerative potential of the adult mammalian heart. We hypothesized that it could similarly hamper the proliferation of cancer cells in the heart. RESULTS: We first used an in vivo genetic model of cancer in mice, in which Cre-mediated recombination results in the overexpression of mutated K-Ras and deletion of p53, to confirm that the heart resists oncogenic events. Despite a comparable extent of recombination in liver, heart, and skeletal muscle, multiple cancers arose at different anatomical sites but never in the heart. In addition, we set up a mouse model of heterotopic heart transplantation to mechanically unload the heart in vivo. In this model, the aorta and pulmonary artery of the transplanted heart are surgically connected with the carotid artery and external jugular vein of the recipient animal, respectively, thereby restoring perfusion in the absence of mechanical load within the left ventricle. In parallel, we used engineered heart tissues in which mechanical load can be controlled at will. In these models, mechanical load inhibited, whereas tissue unloading promoted the proliferation of lung adenocarcinoma, colon carcinoma, and melanoma cells within the myocardium. To investigate the mechanisms underlying these effects, we used spatial transcriptomics to analyze samples of human cancers that gave rise to both cardiac and extracardiac metastases. We found that cardiac metastases shared a common transcriptional profile, independent from the origin of the primary tumor. Among the most up-regulated genes in cardiac metastases were histone demethylases. Consistently, cardiac metastases showed reduced histone 3 lysine 9 trimethylation and reduced chromatin compaction. Similar findings were observed in our experimental models of cardiac load modulation in which chromatin accessibility and histone methylation were altered at sites controlling cancer cell proliferation, as determined by single-nuclei assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing. Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation. Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors. CONCLUSION: Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation. Key mechanisms inhibiting cancer cell proliferation in the heart.: Cancer cells that engraft into the myocardium are exposed to mechanical forces generated by both cardiomyocyte contraction and pressure-volume load. Nesprin-2 is a key molecule in sensing these forces, resulting in reduced histone methylation and chromatin compaction in cancer cells, overall halting their proliferation. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]