Proceedings of the National Academy of Sciences of the United States of America · 2025
Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5.
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Wang Xuefeng, Sun Jian, Lan Bin, Wang Chunyu, Ma Jiayi, Hu Qiaoting, Liu Jun, Cheng Haili, Wen Hong, Lin Jieyu, Ren Xinyi, Yu Huabin, Jiang Menghui, Chen Fangfang, Ye Jiayin, Zhai Jingjie, Lan Haokun, Ouyang Kai, Jing Zihao, Lv Libo, Chen Ying, Zhuo Weibin, Lin Jing, Chen Yu, Lu Jinsong, Shi Yufang, Wang Ying
Аннотация
Cardiac calcification, often seen in age-related diseases, impairs heart function, yet its association with malignant tumors remains largely overlooked. Our study revealed that pericardial calcification (PC) occurs in up to 80% of breast cancer patients with pulmonary metastasis. We demonstrate a reciprocal relationship where breast cancer drives PC, which in turn accelerates cancer progression in humans and mice. Lung metastases increase monocyte-derived macrophage and mesenchymal stem cell (MSC)-derived osteoblast infiltration in the pericardial tissue, triggering inflammation and calcification. Mechanistically, metastatic cancer cells in the lungs highly express and secrete asparagine endopeptidase (AEP), which cleaves IGF2BP3 to free IGF2. AEP and IGF2 contribute to PC by promoting osteoblast differentiation in heart tissue through integrin αvβ5 and IGF1R activation, respectively. Pharmacological blockade of integrin αvβ5 and IGF1R, especially when combined, effectively inhibits ectopic osteogenesis and disrupts the feedback loop between PC and cancer progression. These findings elucidate the interplay between metastatic breast cancer and PC and suggest therapeutic strategies to hinder breast cancer progression.