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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Change history
16 June 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41388-023-02752-0
27 January 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41388-023-02609-6
References
Jaiswal R, Sedger LM. Intercellular vesicular transfer by exosomes, microparticles and oncosomes - implications for cancer biology and treatments. Front Oncol. 2019;9:125.
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:13–16.
You S, Barkalifa R, Chaney EJ, Tu H, Park J, Sorrells JE, et al. Label-free visualization and characterization of extracellular vesicles in breast cancer. Proc Natl Acad Sci USA. 2019;116:24012–8.
Zhao LJ, Li YY, Zhang YT, Fan QQ, Ren HM, Zhang C, et al. Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness. EMBO Rep. 2021;22:e50922.
Sansone P, Savini C, Kurelac I, Chang Q, Amato LB, Strillacci A, et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci USA. 2017;114:E9066–E9075.
Marar C, Starich B, Wirtz D. Extracellular vesicles in immunomodulation and tumor progression. Nat Immunol. 2021;22:560–70.
Sung BH, Parent CA, Weaver AM. Extracellular vesicles: critical players during cell migration. Dev Cell. 2021;56:1861–74.
Sung BH, von Lersner A, Guerrero J, Krystofiak ES, Inman D, Pelletier R, et al. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells. Nat Commun. 2020;11:2092.
Singh A, Fedele C, Lu H, Nevalainen MT, Keen JH, Languino LR. Exosome-mediated transfer of alphavbeta3 integrin from tumorigenic to nontumorigenic cells promotes a migratory phenotype. Mol Cancer Res. 2016;14:1136–46.
Bertolini I, Ghosh JC, Kossenkov AV, Mulugu S, Krishn SR, Vaira V, et al. Small extracellular vesicle regulation of mitochondrial dynamics reprograms a hypoxic tumor microenvironment. Dev Cell. 2020;55:163–77. e166
Ma Y, Dong S, Li X, Kim BYS, Yang Z, Jiang W. Extracellular vesicles: an emerging nanoplatform for cancer therapy. Front Oncol. 2020;10:606906.
Lucien F, Leong HS. The role of extracellular vesicles in cancer microenvironment and metastasis: myths and challenges. Biochem Soc Trans. 2019;47:273–80.
Baram T, Rubinstein-Achiasaf L, Ben-Yaakov H, Ben-Baruch A. Inflammation-driven breast tumor cell plasticity: stemness/emt, therapy resistance and dormancy. Front Oncol. 2020;10:614468.
Caino MC, Seo JH, Aguinaldo A, Wait E, Bryant KG, Kossenkov AV, et al. A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun. 2016;7:13730.
Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer. 2018;18:19–32.
Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y, et al. Extracellular vesicle-packaged HIF-1alpha-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019;21:498–510.
Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5:51–63.
Vaynberg J, Fukuda K, Lu F, Bialkowska K, Chen Y, Plow EF, et al. Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion. Nat Commun. 2018;9:4465.
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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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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DOI: https://doi.org/10.1038/s41388-022-02280-3
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