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Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells

Oncogene volume 41, pages 2624–2637 (2022)Cite this article

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Abstract

Tumor therapeutics often target the primary tumor bulk but fail to eradicate therapy-resistant cancer stem cells (CSCs) in quiescent state. These can then become activated to initiate recurrence and/or metastasis beyond therapy. Here, we identified and isolated chemoradiotherapy-resistant CSCs in quiescent state with high capacity of tumor-initiation and tumorsphere formation from three types of breast tumors in mice. Experiments of knockdown and rescue revealed DEK, a nuclear protein, as essential for CSC activation. Exogenous DEK was then used to trigger quiescence exit of CSCs. ChIP-seq and ATAC-seq showed that DEK directly binds to chromatin, facilitating its genome-wide accessibility. The resulting epigenetic events upregulate the expression of cellular activation-related genes including MYC targets, whereas cellular quiescence-related genes including the p53 signaling pathway are silenced. However, twinned with DEK-induced activation, formerly resistant CSCs were then destroyed by chemotherapy in vitro. In mice, traditional chemoradiotherapy concurrent with the injection of DEK-containing exosomes resulted in eradication of primary tumors together with formerly resistant CSCs without recurrence or metastasis. Our findings advance knowledge of the mechanism of quiescent CSC activation and may provide novel clinical opportunities for removal of quiescence-linked therapy resistance.

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Fig. 1: Identification and isolation of therapy-resistant CSCs in quiescent state from three types of breast tumors in mice.
Fig. 2: Functions of endogenous and exogenous DEK in activation of CSCs.
Fig. 3: DEK directly binds to chromatin, facilitating its genome-wide accessibility.
Fig. 4: DEK regulates global gene expression including upregulated MYC targets and downregulated the p53 signaling pathway.
Fig. 5: Exosomal DEK activates qCSCs and deprives their therapy resistance.
Fig. 6: Exosomal DEK activates qCSCs in vivo and promotes tumor progress, metastasis and relapse.
Fig. 7: Traditional chemoradiotherapy combined with DEK-exosomes eradicates primary tumors together with resistant CSCs without recurrence or metastasis.

References

  1. Holohan C, Schaeybroeck SV, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26.

    Article  CAS  PubMed  Google Scholar 

  2. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81–94.

    Article  CAS  PubMed  Google Scholar 

  3. Marusyk A, Janiszewska M, Polyak K. Intratumor heterogeneity: the Rosetta Stone of therapy resistance. Cancer Cell. 2020;37:471–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bajaj J, Diaz E, Reya T. Stem cells in cancer initiation and progression. J Cell Biol. 2020;219:e201911053.

    Article  PubMed  CAS  Google Scholar 

  5. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019;234:116781.

    Article  CAS  PubMed  Google Scholar 

  6. Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Therapy resistance mediated by cancer stem cells. Semin Cancer Biol. 2018;53:156–67.

    Article  CAS  PubMed  Google Scholar 

  7. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  CAS  PubMed  Google Scholar 

  8. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34.

    Article  CAS  PubMed  Google Scholar 

  9. Khodadoust MS, Verhaegen M, Kappes F, Riveiro-Falkenbach E, Cigudosa JC, Kim DSL, et al. Melanoma proliferation and chemoresistance controlled by the DEK oncogene. Cancer Res. 2009;69:6405–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu S, Wang X, Sun F, Kong J, Li Z, Lin Z. DEK overexpression is correlated with the clinical features of breast cancer. Pathol Int. 2012;62:176–81.

    Article  PubMed  Google Scholar 

  11. Hacker KE, Bolland DE, Tan L, Saha AK, Niknafs YS, Markovitz DM, et al. The DEK oncoprotein functions in ovarian cancer growth and survival. Neoplasia 2018;20:1209–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yi HC, Liu YL, You P, Pan JS, Zhou JY, Liu ZJ, et al. Overexpression of DEK gene is correlated with poor prognosis in hepatocellular carcinoma. Mol Med Rep. 2015;11:1318–23.

    Article  CAS  PubMed  Google Scholar 

  13. Sun J, Bi F, Yang Y, Zhang Y, Jin A, Li J, et al. DEK protein overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma. Oncol Rep. 2017;37:857–64.

    Article  CAS  PubMed  Google Scholar 

  14. Piao J, Shang Y, Liu S, Piao Y, Cui X, Li Y, et al. High expression of DEK predicts poor prognosis of gastric adenocarcinoma. Diagn Pathol. 2014;9:67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Wang X, Lin L, Ren X, Lin Z, Li Z, Li C, et al. High expression of oncoprotein DEK predicts poor prognosis of small cell lung cancer. Int J Clin Exp Pathol. 2014;7:5016–23.

    PubMed  PubMed Central  Google Scholar 

  16. Waldmann T, Scholten I, Kappes F, Hu HG, Knippers R. The DEK protein-an abundant and ubiquitous constituent of mammalian chromatin. Gene. 2004;343:1–9.

    Article  CAS  PubMed  Google Scholar 

  17. Sandén C, Järvstråt L, Lennartsson A, Brattås P, Nilsson B, Gullberg U. The DEK oncoprotein binds to highly and ubiquitously expressed genes with a dual role in their transcriptional regulation. Mol Cancer. 2014;13:215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Sandén C, Gullberg U. The DEK oncoprotein and its emerging roles in gene regulation. Leukemia. 2015;29:1632–6.

    Article  PubMed  CAS  Google Scholar 

  19. Privette Vinnedge LM, Benight NM, Wagh PK, Pease NA, Nashu MA, Serrano-Lopez J, et al. The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. Oncogene. 2015;34:2325–36.

    Article  CAS  PubMed  Google Scholar 

  20. Koleva RI, Ficarro SB, Radomska HS, Carrasco-Alfonso MJ, Alberta JA, Webber JT, et al. C/EBPα and DEK coordinately regulate myeloid differentiation. Blood. 2012;119:4878–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hua Y, Hu H, Peng X. Progress in studies on the DEK protein and its involvement in cellular apoptosis. Sci China Life Sci. 2009;52:637–42.

    Article  CAS  Google Scholar 

  22. Wise-Draper TM, Allen HV, Thobe MN, Jones EE, Habash KB, Münger K, et al. The human DEK proto-oncogene is a senescence inhibitor and an upregulated target of high-risk human papillomavirus E7. J Virol. 2005;79:14309–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kavanaugh GM, Wise-Draper TM, Morreale RJ, Morrison MA, Gole B, Schwemberger S, et al. The human DEK oncogene regulates DNA damage response signaling and repair. Nucleic Acids Res. 2011;39:7465–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dai L, Ye S, Li HW, Chen DF, Wang HL, Jia SN, et al. SETD4 regulates cell quiescence and catalyzes the trimethylation of H4K20 during diapause formation in artemia. Mol Cell Biol. 2017;37:e00453–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ye S, Ding YF, Jia WH, Liu XL, Feng JY, Zhu Q, et al. SET domain–containing protein 4 epigenetically controls breast cancer stem cell quiescence. Cancer Res. 2019;79:4729–43.

    Article  CAS  PubMed  Google Scholar 

  26. Jia WH, Li AQ, Feng JY, Ding YF, Ye S, Yang JS, et al. DEK terminates diapause by activation of quiescent cells in the crustacean Artemia. Biochem J. 2019;476:1753–69.

    Article  CAS  PubMed  Google Scholar 

  27. Zeng X, Liu C, Yao J, Wan H, Wan G, Li Y, et al. Breast cancer stem cells, heterogeneity, targeting therapies and therapeutic implications. Pharm Res. 2021;163:105320.

    Article  CAS  Google Scholar 

  28. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Capitano ML, Mor-Vaknin N, Saha AK, Cooper S, Legendre M, Guo H, et al. Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. J Clin Investig. 2019;129:2555–70.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Saha AK, Kappes F, Mundade A, Deutzmann A, Rosmarin DM, Legendre M, et al. Intercellular trafficking of the nuclear oncoprotein DEK. Proc Natl Acad Sci USA. 2013;110:6847–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Teng Y, Lang L, Jauregui CE. The complexity of DEK signaling in cancer progression. Curr Cancer Drug Targets. 2018;18:256–65.

    Article  CAS  PubMed  Google Scholar 

  33. Mor-Vaknin N, Punturieri A, Sitwala K, Faulkner N, Legendre M, Khodadoust MS, et al. The DEK nuclear autoantigen is a secreted chemotactic factor. Mol Cell Biol. 2006;26:9484–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Recasens A, Munoz L. Targeting cancer cell dormancy. Trends Pharm Sci. 2019;40:128–41.

    Article  CAS  PubMed  Google Scholar 

  35. Sistigu A, Musella M, Galassi C, Vitale I, De Maria R. Tuning cancer fate: tumor microenvironment’s role in cancer stem cell quiescence and reawakening. Front Immunol. 2020;11:2166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Damen MPF, van Rheenen J, Scheele CLGJ. Targeting dormant tumor cells to prevent cancer recurrence. FEBS J. 2021;288:6286–303.

    Article  CAS  PubMed  Google Scholar 

  37. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol. 2010;28:275–80.

    Article  CAS  PubMed  Google Scholar 

  38. Sansone P, Ceccarelli C, Berishaj M, Chang Q, Rajasekhar VK, Perna F, et al. Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer. Nat Commun. 2016;7:10442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell. 2012;150:764–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Boichuk S, Parry JA, Makielski KR, Litovchick L, Baron JL, Zewe JP, et al. The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res. 2013;73:5120–9.

    Article  CAS  PubMed  Google Scholar 

  41. Ewton DZ, Hu J, Vilenchik M, Deng X, Luk KC, Polonskaia A, et al. Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells. Mol Cancer Ther. 2011;10:2104–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Khoo WH, Ledergor G, Weiner A, Roden DL, Terry RL, McDonald MM, et al. A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. Blood. 2019;134:30–43.

    Article  CAS  PubMed  Google Scholar 

  43. Hidayat M, Mitsuishi Y, Takahashi F, Tajima K, Yae T, Miyahara K, et al. Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer. Bosn J Basic Med Sci. 2019;19:355–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Waldmann T, Eckerich C, Baack M, Gruss C. The ubiquitous chromatin protein DEK alters the structure of DNA by introducing positive supercoils. J Biol Chem. 2002;277:24988–94.

    Article  CAS  PubMed  Google Scholar 

  45. Lee MS, Garrard WT. Positive DNA supercoiling generates a chromatin conformation characteristic of highly active genes. Proc Natl Acad Sci USA. 1991;88:9675–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hu HG, Scholten I, Gruss C, Knippers R. The distribution of the DEK protein in mammalian chromatin. Biochem Biophys Res Commun. 2007;358:1008–14.

    Article  CAS  PubMed  Google Scholar 

  47. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta. 2014;1846:75–87.

    CAS  PubMed  Google Scholar 

  48. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10:1213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat. 2010;123:725–31.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Xing-hui Song of the core facilities, Zhejiang University school of medicine, for assistance with fluorescence-activated cell and exosome sorting.

Funding

This work was supported by the National Major Research and Development Project (2016YFA0101201) and the National Natural Science Foundation of China (Project No. 31730084).

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Authors and Affiliations

  1. MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China

    Yao-Shun Yang, Xi-Zheng Jia, Qian-Yun Lu, Sun-Li Cai, Xue-Ting Huang, Shu-Hua Yang, Chris Wood, Jin-Shu Yang & Wei-Jun Yang

  2. Department of Respiratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

    Yue-Hong Wang

  3. Department of Surgical Oncology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

    Jiao-Jiao Zhou & Yi-Ding Chen

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Contributions

WY supervised the research. WY and YY designed the experiments. WY, YY, and CW wrote the manuscript. XJ and SC performed experiments of Western blot and TEM. QL and XH performed experiments of RNAi and exosomes isolation. SY helped with H&E staining and IF analysis. JY helped with the analysis of RNA-seq, ChIP-seq, and ATAC-seq. YW, JZ, and YC provided samples from clinical breast cancer patients and participated in the analysis of clinical data.

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Correspondence to Wei-Jun Yang.

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Yang, YS., Jia, XZ., Lu, QY. et al. Exosomal DEK removes chemoradiotherapy resistance by triggering quiescence exit of breast cancer stem cells. Oncogene 41, 2624–2637 (2022). https://doi.org/10.1038/s41388-022-02278-x

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