@article{Liu2026, 
author = {Liming Liu and Yichu Zhang and Xiaoxue Li and Yueni Mo and Lanlan Song and Yidi Jia and Luoming Zhang and Wei Zhou and He Zhang and Hui Guo and Zhiyong Wang and Yanfen Cui and Fei Zhang and Ruifang Niu},
title = {Exosomal EPHA2 transfers metastatic potential by stabilizing TGF-βRI and activating the TGF-β/SMAD3 signaling pathway in breast cancer},
year = {2026},
journal = {Cancer Biology & Medicine},
volume = {23},
number = {8},
pages = {1128-1155},
keywords = {Breast cancer, intratumor heterogeneity, exosomes, EPHA2, TGF-βRI},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2025.0440},
doi = {10.20892/j.issn.2095-3941.2025.0440},
abstract = {ObjectiveIntratumoral heterogeneity refers to the presence of distinct subpopulations of cancer cells within a single tumor, which exhibits variations in phenotypic traits, such as proliferation rate, drug sensitivity, and metastatic potential. Dynamic interactions among heterogeneous cell populations have a critical role in tumor progression. Increasing evidence underscores the importance of intercellular communication among heterogeneous cancer cell subpopulations in driving malignancy. However, the molecular mechanisms governing such cancer cell-to-cancer cell interactions are poorly understood.MethodsExosomes were isolated from highly metastatic breast cancer cells (HM-BCCs) and low metastatic breast cancer cells (LM-BCCs). The role of exosome-mediated intercellular communication on metastatic behavior was assessed using wound healing and Transwell assays. Gene knockdown and overexpression strategies, small-molecule inhibitors, and xenograft mouse models were used to elucidate the role of exosomal EPHA2.ResultsExosomes derived from HM-BCCs considerably enhanced the migratory and invasive capabilities of LM-BCCs in vitro and increased the metastatic potential in vivo. Mechanistically, EPHA2 was identified as a key protein enriched in exosomes from HM-BCCs and was shown to be transferred to LM-BCCs by these vesicles. Exosomal EPHA2 promoted epithelial-to-mesenchymal transition in LM-BCCs when internalized by stabilizing TGF-βRI and activating the transforming growth factor-β/mothers against decapentaplegic homolog 3 (TGF-β/SMAD3) signaling pathway, thereby facilitating the acquisition of a metastatic phenotype.ConclusionsThe results underscore the pivotal function of exosomal EPHA2 in mediating the transfer of metastatic potential among heterogeneous breast cancer cell populations. Targeting the EPHA2-TGF-βRI signaling axis may provide a novel therapeutic approach for preventing or limiting breast cancer metastasis.}
}