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

A Correction to this article was published on 27 January 2023

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Abstract

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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Fig. 1: Breast cancer-derived sEVHYP activate NFκB in MCF10A recipient cells.
Fig. 2: NFκB regulation of sEVHYP-dependent mitochondrial dynamics and cell motility.
Fig. 3: NFκB regulation of 3D mammary acini morphogenesis.
Fig. 4: sEV-induced EMT in the mammary gland, in vivo.

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Acknowledgements

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.).

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IB, and DCA conceived the project; IB performed experiments of sEV-induced NFκB activation, cytokine modulation, mitochondrial-fueled cell movements and tissue developmental morphogenesis; MP performed experiments of NFκB regulation, and AVK performed bioinformatics analysis. IB and DCA analyzed data and wrote the paper.

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Correspondence to Dario C. Altieri.

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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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