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Exosomal EphA2 promotes tumor metastasis of triple-negative breast cancer by damaging endothelial barrier

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Abstract

Many evidences show that exosomes play an important role in cancer development, invasion and metastasis. This study is based on the need to explore exosomal protein that promote breast cancer metastasis. We found that tyrosine kinase EphA2 was enriched in Triple-negative breast cancer -derived exosomes and it could disrupt the endothelial monolayer barrier through downregulating tight junction proteins of endothelial cells. These mechanisms were confirmed by in vivo experiments. After periodical injection of exosomal EphA2 into mice caudal vein, we found increased vascular permeability and breast cancer metastases in distant organs, and this phenomenon decreased dramatically after exosomal EphA2 knockdown. This study provides a new mechanism of exosome promoting breast cancer metastasis and suggests a new therapeutic target for the prevention and treatment of breast cancer metastasis.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Global cancer statistics, et al (2020) GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 0(0):1–41

    Google Scholar 

  2. Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132

    Article  Google Scholar 

  3. Harbeck N, Gnant M (2017) Breast cancer. Lancet 389(10074):1134–1150

    Article  Google Scholar 

  4. Won KA, Spruck C (2020) Triple-negative breast cancer therapy: current and future perspectives. Int J Oncol 57(6):1245–1261

    Article  CAS  Google Scholar 

  5. van Niel G, D’Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19(4):213–228

    Article  Google Scholar 

  6. Mathieu M, Martin-Jaular L, Lavieu G et al (2019) Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21(1):9–17

    Article  CAS  Google Scholar 

  7. Maziveyi M, Dong S, Baranwal S et al (2019) Exosomes from nischarin-expressing cells reduce breast cancer cell motility and tumor growth. Can Res 79(9):2152–2166

    Article  CAS  Google Scholar 

  8. Wortzel I, Dror S, Kenific CM et al (2019) Exosome-mediated metastasis: communication from a distance. Dev Cell 49(3):347–360

    Article  CAS  Google Scholar 

  9. Scognamiglio I, Cocca L, Puoti I et al (2022) Exosomal microRNAs synergistically trigger stromal fibroblasts in breast cancer. Mol Ther Nucleic Acids 28:17–31

    Article  CAS  Google Scholar 

  10. Fidler IJ (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A Clowes memorial award lecture. Cancer Res 50(19):6130–6138

    CAS  Google Scholar 

  11. Fidler IJ, Poste G (2008) The, “seed and soil” hypothesis revisited. Lancet Oncol 9(8):808

    Article  Google Scholar 

  12. Di Modica M, Regondi V, Sandri M et al (2017) Breast cancer-secreted miR-939 downregulates VE-cadherin and destroys the barrier function of endothelial monolayers. Cancer Lett 384(2):94–100

    Article  Google Scholar 

  13. Zhou W, Fong MY, Min Y et al (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25(4):501–515

    Article  CAS  Google Scholar 

  14. Zeng Z, Li Y, Pan Y et al (2018) Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun 9(1):5395

    Article  CAS  Google Scholar 

  15. Lin Y, Zhang C, Xiang P et al (2020) Exosomes derived from HeLa cells break down vascular integrity by triggering endoplasmic reticulum stress in endothelial cells. J Extracell Vesicles 9(1):1722385

    Article  CAS  Google Scholar 

  16. Cen J, Feng L, Ke H et al (2019) Exosomal thrombospondin-1 disrupts the integrity of endothelial intercellular junctions to facilitate breast cancer cell metastasis. Cancers 11(12):1946–1963

    Article  CAS  Google Scholar 

  17. Zhu Y, Pick H, Gasilova N et al (2019) MALDI detection of exosomes: a potential tool for cancer studies. Chem 5(5):1318–1336

    Article  CAS  Google Scholar 

  18. Hoshino A, Kim HS, Bojmar L et al (2020) Extracellular vesicle and particle biomarkers define multiple human cancers. Cell 182(4):1044–1061

    Article  CAS  Google Scholar 

  19. Pane K, Quintavalle C, Nuzzo S et al (2022) Comparative proteomic profiling of secreted extracellular vesicles from breast fibroadenoma and malignant lesions: a pilot study. Int J Mol Sci 23(7):3989

    Article  CAS  Google Scholar 

  20. Risha Y, Minic Z, Ghobadloo SM et al (2020) The proteomic analysis of breast cell line exosomes reveals disease patterns and potential biomarkers. Sci Rep 10(1):13572

    Article  CAS  Google Scholar 

  21. Théry C, Amigorena S, Raposo G et al (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 30(1):3–22

    Article  Google Scholar 

  22. Janiszewska M, Primi MC, Izard T (2020) Cell adhesion in cancer: beyond the migration of single cells. J Biol Chem 295(8):2495–2505

    Article  CAS  Google Scholar 

  23. Sung JS, Kang CW, Kang S et al (2020) ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene 39(3):664–676

    Article  CAS  Google Scholar 

  24. Tutanov O, Orlova E, Proskura K et al (2020) Proteomic Analysis of Blood Exosomes from healthy females and breast cancer patients reveals an association between different exosomal bioactivity on non-tumorigenic epithelial cell and breast cancer cell migration in vitro. Biomolecules 10(4):495

    Article  CAS  Google Scholar 

  25. Di Modica M, Regondi V, Sandri M et al (2017) Breast cancer-secreted miR-939 downregulates VE-cadherin and destroys the barrier function of endothelial monolayers. Cancer Lett 2017(384):94–100

    Article  Google Scholar 

  26. Fox BP, Kandpal RP (2004) Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun 318(4):882–892

    Article  CAS  Google Scholar 

  27. Li X, Wang L, Gu JW et al (2010) Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumour Biol 31(5):477–488

    Article  CAS  Google Scholar 

  28. Ireton RC, Chen J (2005) EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets 5(3):149–157

    Article  CAS  Google Scholar 

  29. Mo J, Zhao X, Dong X et al (2020) Effect of EphA2 knockdown on melanoma metastasis depends on intrinsic ephrinA1 level. Cell Oncol 43(4):655–667

    Article  CAS  Google Scholar 

  30. Gao Z, Han X, Zhu Y et al (2021) Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling. Cell Death Dis 12(5):414

    Article  CAS  Google Scholar 

  31. Fan J, Wei Q, Koay EJ et al (2018) Chemoresistance transmission via exosome-mediated EphA2 transfer in pancreatic cancer. Theranostics 8(21):5986–5994

    Article  CAS  Google Scholar 

  32. Rüffer C, Strey A, Janning A et al (2004) Cell-cell junctions of dermal microvascular endothelial cells contain tight and adherens junction proteins in spatial proximity. Biochemistry 43(18):5360–5369

    Article  Google Scholar 

  33. Dai W, Nadadur RD, Brennan JA et al (2020) ZO-1 regulates intercalated disc composition and atrioventricular node conduction. Circ Res 127(2):e28–e43

    Article  CAS  Google Scholar 

  34. Anderson JM, Fanning AS, Lapierre L et al (1995) Zonula occludens (ZO)-1 and ZO-2: membrane-associated guanylate kinase homologues (MAGuKs) of the tight junction. Biochem Soc Trans 23(3):470–475

    Article  CAS  Google Scholar 

  35. Larson J, Schomberg S, Schroeder W et al (2008) Endothelial EphA receptor stimulation increases lung vascular permeability. Am J Physiol Lung Cell Mol Physiol 295(3):L431–L439

    Article  CAS  Google Scholar 

  36. Fanning AS, Jameson BJ, Jesaitis LA et al (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273(45):29745–29753

    Article  CAS  Google Scholar 

  37. Settleman J, Albright CF, Foster LC et al (1992) Association between GTPase activators for Rho and Ras families. Nature 359(6391):153–154

    Article  CAS  Google Scholar 

  38. Li J, Li Z, Jiang P et al (2018) Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res 37(1):177

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by Xiamen Key Laboratory of Endocrine-Related Cancer Precision Medicine (XKLEC2021KF02), the Young and Middle-aged Talents Training Program of Fujian Provincial Health Commission (2020GGB062), Natural Science Foundation of Fujian Province (2019J01012) and Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University (PM201809170014).

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Authors and Affiliations

  1. Department of Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China

    Xin Liu, Yue Li, Jie Zhou, Lei Wang & Xinmei Kang

  2. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, Fujian, China

    Chunjing Chen & Xiang Gao

  3. Department of Electronic Science, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, Fujian, China

    Jiyang Dong

  4. School of Medicine, Huaqiao University, Xiamen, 362021, Fujian, China

    Dandan Tong

Authors
  1. Xin Liu
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  2. Yue Li
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  3. Chunjing Chen
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  8. Xiang Gao
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  9. Xinmei Kang
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Contributions

XMK and XG conceived and designed the experiments. XL, YL, CJC and JZ performed the experiments. JYD, DDT and LW analyzed and interpreted the data. XL wrote the original manuscript, XG and XMK edited and revised the manuscript, and all authors reviewed the manuscript and approved of the final version.

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Correspondence to Xiang Gao or Xinmei Kang.

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The authors declare that they have no competing interests.

Ethical approval

All animal experiments were approved by Laboratory Animal Management and Ethics Committee of Xiamen University (Fujian, China).

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Supplementary Information

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10585_2022_10194_MOESM1_ESM.pdf

Supplementary file1 (PDF 71 kb)— Figure S1. Analysis of exosomal proteins derived from breast cancer cell lines by using mass spectrometry. (A) Venn diagram of proteins derived from MCF-7 exosomes with 2 replications; (B) &(C) GO enrichment analysis of exosomal proteins of MDA-MB-231, MCF-10A and MCF-7 cell lines. MF: Molecular function; CC: Cellular component.

Supplementary file2 (DOCX 16 kb)

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Liu, X., Li, Y., Chen, C. et al. Exosomal EphA2 promotes tumor metastasis of triple-negative breast cancer by damaging endothelial barrier. Clin Exp Metastasis 40, 105–116 (2023). https://doi.org/10.1007/s10585-022-10194-3

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  • DOI: https://doi.org/10.1007/s10585-022-10194-3

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