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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE285907 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChipÂ® arrays.

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

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