NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment

Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEV(HYP)), but not normoxic (sEV(NORM)) conditions activate NF kappa B in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEV(HYP) via HIF1 alpha is sufficient to activate NF kappa B in the normal mammary epithelium, in vivo. Therefore, sEV(HYP) activation of NF kappa B drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.