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Exosomal EPHA2 transfers metastatic potential by stabilizing TGF-βRI and activating the TGF-β/SMAD3 signaling pathway in breast cancer 认领 引用
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作者 Liming Liu Yichu Zhang +11 位作者 Xiaoxue Li Yueni Mo Lanlan Song Yidi Jia Luoming Zhang Wei Zhou He Zhang Hui Guo Zhiyong Wang Yanfen Cui Fei Zhang Ruifang Niu 《Cancer Biology & Medicine》 SCIE CAS CSCD 2026年第8期1128-1155,I0004-I0009,共28页
Objective:Intratumoral 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,a... Objective:Intratumoral 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.Methods:Exosomes 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.Results:Exosomes 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.Conclusions:The 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. 展开更多
关键词 Breast cancer intratumor heterogeneity exosomes EPHA2 TGF-βRI
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