Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5

Cardiac calcification, commonly observed in age-related diseases, impairs heart function. However, its link to malignant tumors is poorly understood. Our study revealed that pericardial metallization occurs in up to 80% of breast cancer patients with pulmonary metastasis. We demonstrate a reciprocal relationship where breast cancer promotes pericardial calcification, which in turn accelerates cancer progression in both human patients and mice. Lung metastases increase macrophage and pre-osteoblast infiltration in the pericardial tissue, triggering inflammation and osteogenesis. Mechanistically, metastatic cancer cells in lungs highly express asparagine endopeptidase (AEP), which cleaves IGF2BP3 to enhance IGF2 level within these cells’ selves. These secreted AEP and IGF2 contribute to pericardial calcification by promoting osteoblast differentiation in heart tissue through activation of integrin αvβ5 and IGF1R respectively. Pharmacological inhibition of integrin αvβ5 and IGF1R effectively suppressed ectopic osteogenesis and disrupts the feedback loop from pericardial calcification to cancer progression. Taken together, these findings underscore the significance of managing pericardial calcification in breast cancer patients and offer potential treatment strategies.