Asparagine endopeptidase prompts breast cancer–related pericardial calcification by regulating IGF2 and integrin αvβ5
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (27)
Xuefeng Wang
Beijing National Laboratory for Condensed Matter Physics
Jian Sun
Bin Lan
National Health Commission Key Laboratory of Cancer Metabolism, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Chunyu Wang
Center for Biotechnology and Interdisciplinary Studies
Jiayi Ma
Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University
Qiaoting Hu
National Health Commission Key Laboratory of Cancer Metabolism, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Jun Liu
Haili Cheng
National Health Commission Key Laboratory of Cancer Metabolism, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Hong Wen
Jieyu Lin
National Health Commission Key Laboratory of Cancer Metabolism, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Xinyi Ren
Xiamen University-Fujian Cancer Hospital Research Center of Metabolism and Cancer, State Key Laboratory for Cellular Stress Biology, Xiamen University
Huabin Yu
Xiamen University-Fujian Cancer Hospital Research Center of Metabolism and Cancer, State Key Laboratory for Cellular Stress Biology, Xiamen University
Menghui Jiang
School of Public Health, Qingdao University
Fangfang Chen
Jiayin Ye
Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
Jingjie Zhai
Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
Haokun Lan
Interdisciplinary Institute for Medical Engineering, Fuzhou University
Kai Ouyang
Xiamen University-Fujian Cancer Hospital Research Center of Metabolism and Cancer, State Key Laboratory for Cellular Stress Biology, Xiamen University
Zihao Jing
Xiamen University-Fujian Cancer Hospital Research Center of Metabolism and Cancer, State Key Laboratory for Cellular Stress Biology, Xiamen University
Libo Lv
Xiamen University-Fujian Cancer Hospital Research Center of Metabolism and Cancer, State Key Laboratory for Cellular Stress Biology, Xiamen University
Ying Chen
Weibin Zhuo
National Health Commission Key Laboratory of Cancer Metabolism, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Jing Lin
Yu Chen
Jinsong Lu
Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University
Yufang Shi
The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine of Soochow University
Ying Wang