Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

This article has been updated


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Change history


  1. Jaiswal R, Sedger LM. Intercellular vesicular transfer by exosomes, microparticles and oncosomes - implications for cancer biology and treatments. Front Oncol. 2019;9:125.

    Article  Google Scholar 

  2. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:13–16.

    Article  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. Marar C, Starich B, Wirtz D. Extracellular vesicles in immunomodulation and tumor progression. Nat Immunol. 2021;22:560–70.

    Article  CAS  Google Scholar 

  7. Sung BH, Parent CA, Weaver AM. Extracellular vesicles: critical players during cell migration. Dev Cell. 2021;56:1861–74.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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

    Article  CAS  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. Lucien F, Leong HS. The role of extracellular vesicles in cancer microenvironment and metastasis: myths and challenges. Biochem Soc Trans. 2019;47:273–80.

    Article  CAS  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer. 2018;18:19–32.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5:51–63.

    Article  CAS  Google Scholar 

  18. 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.

    Article  Google Scholar 

Download references


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.).

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Dario C. Altieri.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links