A novel peptide MIB1-223aa encoded by exosomal circMIB1 from cancer-associated fibroblasts drives triple-negative breast cancer metastasis and stemness via stabilizing MIB1 to activate Notch signaling

作者：Fangzhou Ye, Yiran Liang, Jianing Wang, Jiayin Song, Yuhan Jin, Lei Wang, Dan Luo, Xiaoyan Li, Yaming Li, Dianwen Han, Tong Chen, Bing Chen, Wenjing Zhao, Lijuan Wang, Qifeng Yang · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.06.023 · 被引用次数：12 · 研究领域：Circular RNAs in diseases、GDF15 and Related Biomarkers、Connective Tissue Growth Factor Research

INTRODUCTION: Emerging evidence has indicated that the complex interactions between tumor microenvironment (TME) and cancer cells play a pivotal role in driving tumor initiation and metastasis. Cancer associated fibroblasts (CAFs), major cell components in the TME, exert significant effects on malignant behaviors of various cancers. Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer with a high metastatic potential and poorer prognosis. However, the underlying mechanism by which CAFs promote TNBC development has not been sufficiently studied. OBJECTIVES: The study aims to elucidate how CAFs promote TNBC aggressiveness by delivering protein-coding circMIB1 to activate MIB1/DLL4/Notch pathway, and provide a potential clinical biomarker for TNBC management. METHODS: The oncogenic exosomal circMIB1 with protein-coding potential was identified through high-throughput RNA sequencing and ribosome nascent-chain complex sequencing (RNC-seq). The enrichment of circMIB1 in CAFs was confirmed using in situ hybridization (ISH) and qRT-PCR. The protein-coding capacity of circMIB1 was validated based on the polysome profiling, and luciferase assays. Functional roles of circMIB1 were explored using in vitro and in vivo models, while the underlying mechanism was dissected via co-immunoprecipitation (Co-IP) and western blotting. RESULTS: CAF-secreted exosomal circMIB1 promoted TNBC metastasis and stemness by translating a functional peptide, MIB1-223aa. Mechani...