Advertisement

Microchimica Acta

, 186:439 | Cite as

Amplified fluorescence imaging of HER2 dimerization on cancer cells by using a co-localization triggered DNA nanoassembly

  • Tiantian Yang
  • Lulu Xu
  • Shengchun Liu
  • Yifan Shen
  • Lizhen Huang
  • Lutan Zhang
  • Shijia DingEmail author
  • Wei ChengEmail author
Original Paper
  • 28 Downloads

Abstract

Convenient and sensitive detection of human epidermal growth factor receptor 2 (HER2) dimerization is highly desirable for molecule subtyping and guiding personalized HER2 targeted therapy of breast cancer. A colocalization-triggered DNA nanoassembly (CtDNA) strategy was developed for amplified imaging of HER2 dimerization. It exploits (a) the advantage of the specificity of aptamer proximity hybridization, and (b) the high sensitivity of hairpin-free nonlinear HCR. The mechanism of step-by-step hairpin-free nonlinear HCR for DNA dendritic nanoassembly was studied by native polyacrylamide gel electrophoresis, atomic force microscopy and fluorometry. The results revealed a high specificity, sensitivity, and excellent controllability of the DNA dendritic nanoassembly. The method was used to identify HER2 homodimers and HER2/HER3 heterodimers in various breast cancer cell lines using fluorescence microscopy. It was then extended to image and quantitatively evaluate HER2 homodimers in clinical formalin-fixed paraffin-embedded breast cancer tissue specimens. This revealed its remarkable accuracy and practicality for clinical diagnostics.

Graphical abstract

Schematic presentation of amplified imaging of human epidermal growth factor receptor 2 (HER2) dimerization on cancer cell surfaces by using a co-localization triggered DNA nanoassembly (CtDNA).

Keywords

HER2 dimerization Fluorescent imaging Aptamer Proximity hybridization Hairpin-free nonlinear HCR DNA nanoassembly Formalin-fixed paraffin-embedded tissue Breast cancer Cancer diagnostics 

Notes

Acknowledgments

This work was funded by the National Natural Science Foundation of China (81572080, 81873972 and 81873980) and the Training Program for Advanced Young Medical Personnel of Chongqing (2017HBRC003).

Compliance with ethical standards

The author(s) declare that they have no competing interests.

Supplementary material

604_2019_3549_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1.30 mb)

References

  1. 1.
    Bondza S, Bjorkelund H, Nestor M, Andersson K, Buijs J (2017) Novel real-time proximity assay for characterizing multiple receptor interactions on living cells. Anal Chem 89(24):13212–13218.  https://doi.org/10.1021/acs.analchem.7b02983 CrossRefPubMedGoogle Scholar
  2. 2.
    Marianayagam NJ, Sunde M, Matthews JM (2004) The power of two: protein dimerization in biology. Trends Biochem Sci 29(11):618–625.  https://doi.org/10.1016/j.tibs.2004.09.006 CrossRefPubMedGoogle Scholar
  3. 3.
    Heldin CH (1995) Dimerization of cell surface receptors in signal transduction. Cell 80(2):213–223.  https://doi.org/10.1016/0092-8674(95)90404-2 CrossRefPubMedGoogle Scholar
  4. 4.
    Geng L, Wang Z, Jia X, Han Q, Xiang Z, Li D, Yang X, Zhang D, Bu X, Wang W, Hu Z, Fang Q (2016) HER2 targeting peptides screening and applications in tumor imaging and drug delivery. Theranostics 6(8):1261–1273.  https://doi.org/10.7150/thno.14302 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tai W, Mahato R, Cheng K (2010) The role of HER2 in cancer therapy and targeted drug delivery. J Control Release 146(3):264–275.  https://doi.org/10.1016/j.jconrel.2010.04.009 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yamaguchi H, Chang SS, Hsu JL, Hung MC (2014) Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 33(9):1073–1081.  https://doi.org/10.1038/onc.2013.74 CrossRefPubMedGoogle Scholar
  7. 7.
    Pohlmann PR, Mayer IA, Mernaugh R (2009) Resistance to Trastuzumab in breast Cancer. Clin Cancer Res 15(24):7479–7491.  https://doi.org/10.1158/1078-0432.ccr-09-0636 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yoshioka Y, Suzuki T, Matsuo Y, Tsurita G, Watanabe T, Dohmae N, Nakamura Y, Hamamoto R (2017) Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization. Cancer med 6(7):1665–1672.  https://doi.org/10.1002/cam4.1099 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Citri A, Skaria KB, Yarden Y (2003) The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 284(1):54–65.  https://doi.org/10.1016/s0014-4827(02)00101-5 CrossRefPubMedGoogle Scholar
  10. 10.
    Ghosh R, Narasanna A, Wang SE, Liu S, Chakrabarty A, Balko JM, Gonzalez-Angulo AM, Mills GB, Penuel E, Winslow J, Sperinde J, Dua R, Pidaparthi S, Mukherjee A, Leitzel K, Kostler WJ, Lipton A, Bates M, Arteaga CL (2011) Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res 71(5):1871–1882.  https://doi.org/10.1158/0008-5472.can-10-1872 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dey N, Williams C, Leyland-Jones B, De P (2015) A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. Am J Transl Res 7(4):733–750PubMedPubMedCentralGoogle Scholar
  12. 12.
    Spears M, Taylor KJ, Munro AF, Cunningham CA, Mallon EA, Twelves CJ, Cameron DA, Thomas J, Bartlett JM (2012) In situ detection of HER2:HER2 and HER2:HER3 protein-protein interactions demonstrates prognostic significance in early breast cancer. Breast Cancer Res Treat 132(2):463–470.  https://doi.org/10.1007/s10549-011-1606-z CrossRefPubMedGoogle Scholar
  13. 13.
    Koos B, Andersson L, Clausson CM, Grannas K, Klaesson A, Cane G, Soderberg O (2014) Analysis of protein interactions in situ by proximity ligation assays. Curr Top Microbiol Immunol 377:111–126.  https://doi.org/10.1007/82_2013_334 CrossRefPubMedGoogle Scholar
  14. 14.
    Avin A, Levy M, Porat Z, Abramson J (2017) Quantitative analysis of protein-protein interactions and post-translational modifications in rare immune populations. Nat Commun 8(1):1524.  https://doi.org/10.1038/s41467-017-01808-6 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liang H, Chen S, Li P, Wang L, Li J, Li J, Yang H-H, Tan W (2018) Nongenetic approach for imaging protein dimerization by aptamer recognition and proximity-induced DNA assembly. J Am Chem Soc 140(12):4186–4190.  https://doi.org/10.1021/jacs.7b11311 CrossRefPubMedGoogle Scholar
  16. 16.
    Wang L, Li W, Sun J, Zhang S-Y, Yang S, Li J, Li J, Yang H-H (2018) Imaging of receptor dimers in zebrafish and living cells via aptamer recognition and proximity-induced hybridization chain reaction. Anal Chem 90(24):14433–14438.  https://doi.org/10.1021/acs.analchem.8b04015 CrossRefPubMedGoogle Scholar
  17. 17.
    Ang YS, Li JJ, Chua PJ, Ng CT, Bay BH, Yung LL (2018) Localized visualization and autonomous detection of cell surface receptor clusters using DNA proximity circuit. Anal Chem 90(10):6193–6198.  https://doi.org/10.1021/acs.analchem.8b00722 CrossRefPubMedGoogle Scholar
  18. 18.
    Hagemann IS (2016) Molecular testing in breast Cancer a guide to current practices. Arch Pathol Lab Med 140(8):815–824.  https://doi.org/10.5858/arpa.2016-0051-RA CrossRefPubMedGoogle Scholar
  19. 19.
    Meng H-M, Liu H, Kuai H, Peng R, Mo L, Zhang X-B (2016) Aptamer-integrated DNA nanostructures for biosensing, bioimaging and cancer therapy. Chem Soc Rev 45(9):2583–2602.  https://doi.org/10.1039/c5cs00645g CrossRefPubMedGoogle Scholar
  20. 20.
    Hong F, Zhang F, Liu Y, Yan H (2017) DNA origami: scaffolds for creating higher order structures. Chem Rev 117(20):12584–12640.  https://doi.org/10.1021/acs.chemrev.6b00825 CrossRefPubMedGoogle Scholar
  21. 21.
    Qu Y, Yang J, Zhan P, Liu S, Zhang K, Jiang Q, Li C, Ding B (2017) Self-assembled DNA dendrimer nanoparticle for efficient delivery of Immunostimulatory CpG motifs. ACS Appl Mater Inter 9(24):20324–20329.  https://doi.org/10.1021/acsami.7b05890 CrossRefGoogle Scholar
  22. 22.
    Xuan F, Fan TW, Hsing IM (2015) Electrochemical interrogation of kinetically-controlled dendritic DNA/PNA assembly for immobilization-free and enzyme-free nucleic acids sensing. ACS Nano 9(5):5027–5033.  https://doi.org/10.1021/nn507282f CrossRefPubMedGoogle Scholar
  23. 23.
    Chang CC, Chen CY, Chuang TL, Wu TH, Wei SC, Liao H, Lin CW (2016) Aptamer-based colorimetric detection of proteins using a branched DNA cascade amplification strategy and unmodified gold nanoparticles. Biosens Bioelectron 78:200–205.  https://doi.org/10.1016/j.bios.2015.11.051 CrossRefPubMedGoogle Scholar
  24. 24.
    Yan Z, Hu S, Wang H, Yu K, Yan G, Liu X, Na L, Feng L (2017) DNA dendrimer–streptavidin Nanocomplex: an efficient signal amplifier for construction of biosensing platforms. Anal Chem 89(12):6907–6914.  https://doi.org/10.1021/acs.analchem.7b01551 CrossRefGoogle Scholar
  25. 25.
    Xuan F, Hsing IM (2014) Triggering hairpin-free chain-branching growth of fluorescent DNA dendrimers for nonlinear hybridization chain reaction. J Am Chem Soc 136(28):9810–9813.  https://doi.org/10.1021/ja502904s CrossRefPubMedGoogle Scholar
  26. 26.
    Ding X, Cheng W, Li Y, Wu J, Li X, Cheng Q, Ding S (2017) An enzyme-free surface plasmon resonance biosensing strategy for detection of DNA and small molecule based on nonlinear hybridization chain reaction. Biosens Bioelectron 87:345–351.  https://doi.org/10.1016/j.bios.2016.08.077 CrossRefPubMedGoogle Scholar
  27. 27.
    Chen CH, Chernis GA, Hoang VQ, Landgraf R (2003) Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci U S A 100(16):9226–9231.  https://doi.org/10.1073/pnas.1332660100 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shi Y, Huang W, Tan Y, Jin X, Dua R, Penuel E, Mukherjee A, Sperinde J, Pannu H, Chenna A, DeFazio-Eli L, Pidaparthi S, Badal Y, Wallweber G, Chen L, Williams S, Tahir H, Larson J, Goodman L, Whitcomb J, Petropoulos C, Winslow J (2009) A novel proximity assay for the detection of proteins and protein complexes: quantitation of HER1 and HER2 total protein expression and homodimerization in formalin-fixed, paraffin-embedded cell lines and breast cancer tissue. Diagn Mol Pathol 18(1):11–21.  https://doi.org/10.1097/PDM.0b013e31818cbdb2 CrossRefPubMedGoogle Scholar
  29. 29.
    Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D, Chen Y, Wang H, Liang J, Das R, Mosher R, Gu J, Huang A, Haubst N, Zehetmeier C, Haberl M, Elis W, Kunz C, Heidt AB, Herlihy K, Murtie J, Schuller A, Arteaga CL, Sellers WR, Ettenberg SA (2013) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 73(19):6024–6035.  https://doi.org/10.1158/0008-5472.can-13-1198 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Okita R, Mougiakakos D, Ando T, Mao Y, Sarhan D, Wennerberg E, Seliger B, Lundqvist A, Mimura K, Kiessling R (2012) HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule a and B expression in human breast cancer cell lines. J Immunol 188(5):2136–2145.  https://doi.org/10.4049/jimmunol.1102237 CrossRefPubMedGoogle Scholar
  31. 31.
    Teng Y, Pi W, Wang Y, Cowell JK (2016) WASF3 provides the conduit to facilitate invasion and metastasis in breast cancer cells through HER2/HER3 signaling. Oncogene 35(35):4633–4640.  https://doi.org/10.1038/onc.2015.527 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 36(20):2105–2122.  https://doi.org/10.1200/jco.2018.77.8738 CrossRefGoogle Scholar
  33. 33.
    Huang W, Reinholz M, Weidler J, Yolanda L, Paquet A, Whitcomb J, Lingle W, Jenkins RB, Chen B, Larson JS, Tan Y, Sherwood T, Bates M, Perez EA (2010) Comparison of central HER2 testing with quantitative total HER2 expression and HER2 homodimer measurements using a novel proximity-based assay. Am J Clin Pathol 134(2):303–311.  https://doi.org/10.1309/ajcp3bzy4yafntrg CrossRefPubMedGoogle Scholar
  34. 34.
    Zhou W, Xu F, Li D, Chen Y (2018) Improved detection of HER2 by a quasi-targeted proteomics approach using aptamer-peptide probe and liquid chromatography-tandem mass spectrometry. Clin Chem 64(3):526–535.  https://doi.org/10.1373/clinchem.2017.274266 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The Center for Clinical Molecular Medical detectionThe First Affiliated Hospital of Chongqing Medical UniversityChongqingPeople’s Republic of China
  2. 2.Department of Endocrine and Breast Surgery, The First Affiliated HospitalChongqing Medical UniversityChongqingPeople’s Republic of China
  3. 3.Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory MedicineChongqing Medical UniversityChongqingPeople’s Republic of China

Personalised recommendations