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 (sEVHYP), but not normoxic (sEVNORM) conditions activate NFκB 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 sEVHYP via HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEVHYP activation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.
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We thank James Hayden and Frederick Keeney of the Wistar Imaging Core Shared Resource for assistance with time-lapse videomicroscopy and Sudheer Mulugu of the Electron Microscopy Resource Lab, Perelman School of Medicine, University of Pennsylvania for cryo-electron microscopy. This work was supported by National Institutes of Health (NIH) grants P01 CA140043, R35 CA220446 (D.C.A.), R50 CA211199 (A.V.K.) and an award from the Mary Kay Foundation (D.C.A.).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Bertolini, I., Perego, M., Ghosh, J.C. et al. NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment. Oncogene 41, 2520–2525 (2022). https://doi.org/10.1038/s41388-022-02280-3
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