Abstract 10825: Tumor-Bearing Induces Cardiomyopathy by Disrupting Cardiometabolic Reprogramming

Abstract

Introduction: Advances in cancer therapies have significantly improved patient survival. However, prolonged tumor-bearing (TB) survival makes the originally hidden cardiovascular disease become an increasingly important cause of death in tumor patients. In addition, some commonly used chemotherapeutic agents, such as the doxorubicin (DOX), have definite cardiotoxicity. Moreover, epidemiological studies found higher risks of cardiovascular disease in cancer patients than in the general population. This study aimed to investigate the if the TB state leads to cardio-fragility and myocardial sensitivity which further causes excessive cardiotoxicity of DOX in tumor patients. Methods and Results: We established mouse TB models with six types of transplantation tumors. We administrated them and littermate controls with DOX intraperitoneal injections of 10mg/kg weekly for four weeks. The results showed more severer myocardial injury in TB mice than control group based on the echocardiography, cardiac fibrosis, and etc. The RNA-seq, extracellular flux analysis, and PET-CT indicated an increased proportion of myocardial glycolytic metabolism in the TB state. Furthermore, the Secretomic results of clinical cancer patients and control group, along with the Co-IP of TB mice, showed that the TB state induced hyper-phosphorylation of protein tyrosine residues in cardiomyocytes (CMs) via the increase of secreted growth factors, which introduced an elevated expression of pyruvate kinase muscle 2 (PKM2) and increased the proportion of dimer conformation. Meanwhile, those changes allowing re-entry of CMs into the cell cycle and further increased DNA damage co-localization with EdU, eventually led to excessive cardiotoxicity in the TB state by DOX. Finally, treatment with AG-1478 or TEPP-46 with DOX restricted the cardiotoxicity in the TB state, which meanwhile enhanced the tumor-suppressive effect in lung cancer and melanoma models. Conclusion: Our study reveals that differences in tyrosine phosphorylation of CMs between TB and normal states could cause metabolic pattern shift and cell cycle re-entry in CMs. The increased cardio-fragility induced by TB state may be involved in the enhanced cardiotoxic side effects of chemotherapeutics.