The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked kinase (ILK) as the most upregulated pathway in sEV-treated epithelial cells, and genetic or pharmacologic targeting of ILK reversed mitochondrial reprogramming and suppressed sEV-induced cell movements. In a three-dimensional (3D) model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death and/or cell proliferation, loss of apical-basal polarity, and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEVs released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium.

肿瘤细胞和邻近正常上皮之间的串扰有助于癌症的进展，但其调节因子仍然难以捉摸。在这里，我们表明，维持在缺氧状态的乳腺癌细胞会释放小的细胞外囊泡（sEV），这些囊泡会激活线粒体动力学，刺激线粒体运动，并促进正常乳腺上皮细胞皮质细胞骨架上的细胞器积累。这会导致 AKT 丝氨酸/苏氨酸激酶 (Akt) 激活、膜粘着斑更新和上皮细胞迁移增加。RNA 测序分析确定整合素连接激酶 (ILK) 是 sEV 处理的上皮细胞中最上调的途径，ILK 的遗传或药理学靶向可逆转线粒体重编程并抑制 sEV 诱导的细胞运动。在乳腺形态发生的三维 (3D) 模型中，sEV 治疗诱导了恶性转化的标志，包括细胞死亡和/或细胞增殖失调、顶端-基底极性丧失以及上皮间质转化 (EMT) 的出现。 ) 标记。因此，缺氧乳腺癌细胞释放的 sEV 会重新编程线粒体动力学，并诱导正常乳腺上皮发生致癌变化。