SMALL EXTRACELLULAR VESICLE REGULATION OF MITOCHONDRIAL DYNAMICS REPROGRAMS A HYPOXIC TUMOR MICROENVIRONMENT

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 (sEV) that activate mitochondrial dynamics, stimulate mitochondrial movements and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in Akt activation, membrane focal adhesion turnover and increased epithelial cell migration. RNA-Seq 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 model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death/cell proliferation, loss of apical-basal polarity and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEV released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium Overall design: RNA-seq analysis of MCF10A cells treated by extracellular vesicles obtained from tumor cells MCF7 under normal and hypoxic conditions