Multi-omics data reveal the origin of cardiac myxoma

Cardiac myxoma, the most common primary cardiac tumor, presents significant challenges due to its molecular complexity, including heterogeneous cellular composition and poorly characterized signaling pathways. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq), third-generation transcriptomics, and untargeted metabolomics to elucidate the cellular origin and molecular pathology of cardiac myxoma. This study provides robust, single-cell-level evidence that cardiac myxomas originate from endothelial cells. Abnormal endothelial-to-mesenchymal transition (EndMT) is a major factor contributing to the coexistence of endothelial and mesenchymal characteristics in myxomas. Additionally, activation of the MET-PTK2 signaling axis may play a key role in the occurrence and progression of myxoma. Pseudotime trajectory analysis revealed a transition from an endothelial-mesenchymal phenotype to a metabolically active state, shedding light on the dynamic changes underlying myxoma progression. Our findings also identify two distinct myxoma subtypes, each characterized by unique molecular features, which highlight different therapeutic opportunities. The third-generation transcriptomics analysis emphasizes the significance of extracellular matrix remodeling and endothelial signaling in tumor development, while metabolomics uncovers substantial alterations in purine, nicotinic acid, and nicotinamide metabolism, pointing to unique metabolic adaptations by myxoma cells. This detailed characterization of cardiac myxoma provides a molecular framework for understanding this rare tumor. Our findings support personalized treatment strategies, including targeting metabolic and signaling pathways, and lay the foundation for future interventions.