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Aberrantly expressed Bruton’s tyrosine kinase preferentially drives metastatic and stem cell-like phenotypes in neuroblastoma cells

Cellular Oncology volume 43, pages 1067–1084 (2020)Cite this article

Abstract

Purpose

Neuroblastoma, a common childhood tumor, remains one of the most elusive diseases to treat. To date, high-risk neuroblastoma is associated with low survival rates. To address this, novel and more effective therapeutic strategies must continue to be explored.

Methods

We employed a bioinformatics approach corroborated with in vitro and in vivo data. Samples from neuroblastoma patients were retrieved and immuno-stained for Bruton’s tyrosine kinase (BTK). To evaluate its effect on cellular functions, BTK expression in SK-N-BE(2) and SH-SY5Y neuroblastoma cells was downregulated using gene silencing or inhibition with ibrutinib or acalabrutinib. Xenograft mouse models were used to investigate the in vivo role of BTK in neuroblastoma tumorigenesis.

Results

We found that BTK was highly expressed in primary neuroblastoma samples, preferentially in MYCN-amplified neuroblastoma cases, and was associated with a poor prognosis. Immunohistochemical staining of tissues from our neuroblastoma cohort revealed a strong BTK immunoreactivity. We also found that neuroblastoma SK-N-BE(2) and SH-SY5Y cells were sensitive to treatment with ibrutinib and acalabrutinib. Pharmacologic or molecular inhibition of BTK elicited a reduction in the migratory and invasive abilities of neuroblastoma cells, and ibrutinib considerably attenuated the neurosphere-forming ability of neuroblastoma cells. Both inhibitors showed synergism with cisplatin. In vivo assays showed that acalabrutinib effectively inhibited neuroblastoma tumorigenesis.

Conclusions

From our data we conclude that BTK is a therapeutically targetable driver of neuroblastoma.

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Data availability

The datasets used and analyzed in the study are available from the corresponding author upon reasonable requests.

References

  1. M.A. Smith, S.F. Altekruse, P.C. Adamson, G.H. Reaman, N.L. Seibel, Declining childhood and adolescent cancer mortality. Cancer 120, 2497–2506 (2014). doi:https://doi.org/10.1002/cncr.28748

    Article  PubMed  PubMed Central  Google Scholar 

  2. K.K. Matthay, J.M. Maris, G. Schleiermacher, A. Nakagawara, C.L. Mackall, L. Diller, W.A. Weiss, Neuroblastoma. Nature reviews. Dis. Prim. 2, 16078 (2016). https://doi.org/10.1038/nrdp.2016.78

    Article  Google Scholar 

  3. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation Cell 144, 646–674 (2011). https://doi.org/10.1016/j.cell.2011.02.013

  4. J.A. Burger, A. Wiestner, Targeting b cell receptor signalling in cancer: Preclinical and clinical advances. Nat. Rev. Cancer 18, 148–167 (2018). https://doi.org/10.1038/nrc.2017.121

    Article  CAS  PubMed  Google Scholar 

  5. A. Wiestner, The role of b-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica 100, 1495–1507 (2015). https://doi.org/10.3324/haematol.2014.119123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. A. Wiestner, Clinical trial data on the BTK pathway in b-cell malignancies. Clin. Adv. Hematol. & Oncol. 11 (Suppl 9), 6–10 (2013)

  7. A. Paulus, S. Akhtar, H. Yousaf, A. Manna, S.M. Paulus, Y. Bashir, T.R. Caulfield, M. Kuranz-Blake, K. Chitta, X. Wang, Y. Asmann, R. Hudec, W. Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment. Springer, S. Ailawadhi and A. Chanan-Khan, Blood Cancer J. 7, e565 (2017). https://doi.org/10.1038/bcj.2017.40

  8. K. Kondo, H. Shaim, P.A. Thompson, J.A. Burger, M. Keating, Z. Estrov, D. Harris, E. Kim, A. Ferrajoli, M. Daher, R. Basar, M. Muftuoglu, N. Imahashi, A. Alsuliman, C. Sobieski, E. Gokdemir, W. Wierda, N. Jain, E. Liu, E.J. Shpall, K. Rezvani, Ibrutinib modulates the immunosuppressive cll microenvironment through stat3-mediated suppression of regulatory b-cell function and inhibition of the pd-1/pd-l1 pathway. Leukemia 32, 960–970 (2018). https://doi.org/10.1038/leu.2017.304

  9. R.W. Hendriks, S. Yuvaraj, L.P. Kil, Targeting bruton’s tyrosine kinase in b cell malignancies. Nat. Rev. Cancer 14, 219–232 (2014). https://doi.org/10.1038/nrc3702

    Article  CAS  PubMed  Google Scholar 

  10. Y. Qiu, H.J. Kung, Signaling network of the BTK family kinases. Oncogene 19, 5651–5661 (2000). https://doi.org/10.1038/sj.onc.1203958

    Article  CAS  PubMed  Google Scholar 

  11. P.A. Thompson, J.A. Burger, Bruton’s tyrosine kinase inhibitors: First and second generation agents for patients with chronic lymphocytic leukemia (cll). Expert. Opin. Investig. Drugs 27, 31–42 (2018). https://doi.org/10.1080/13543784.2018.1404027

    Article  CAS  PubMed  Google Scholar 

  12. H. Qin, G. Wei, I. Sakamaki, Z. Dong, W.A. Cheng, D.L. Smith, F. Wen, H. Sun, K. Kim, S. Cha, L. Bover, S.S. Neelapu, L.W. Kwak, Novel baff-receptor antibody to natively folded recombinant protein eliminates drug-resistant human b-cell malignancies in vivo. Clin. Cancer Res. 24, 1114–1123 (2018). https://doi.org/10.1158/1078-0432.CCR-17-1193

    Article  CAS  PubMed  Google Scholar 

  13. Y. Ge, C. Wang, S. Song, J. Huang, Z. Liu, Y. Li, Q. Meng, J. Zhang, J. Yao, K. Liu, X. Ma, X. Sun, Identification of highly potent BTK and jak3 dual inhibitors with improved activity for the treatment of b-cell lymphoma. Eur. J. Med. Chem. 143, 1847–1857 (2018). https://doi.org/10.1016/j.ejmech.2017.10.080

    Article  CAS  PubMed  Google Scholar 

  14. T. Yano, Chronic lymphocytic leukemia: Biology, disease progression, and current treatment strategies. Jpn. J. Clin. Hematol. 58, 1960–1972 (2017). https://doi.org/10.11406/rinketsu.58.1960

  15. K. Izutsu, Treatment for mantle cell lymphoma. Jpn. J. Clin Hematol. 58, 2026–2032 (2017). https://doi.org/10.11406/rinketsu.58.2026

  16. J. Wu, M. Zhang, D. Liu, Bruton tyrosine kinase inhibitor ono/gs-4059: From bench to bedside. Oncotarget 8, 7201–7207 (2017). https://doi.org/10.18632/oncotarget.12786

    Article  PubMed  Google Scholar 

  17. J.J. Castillo, S.P. Treon, M.S. Davids, Inhibition of the bruton tyrosine kinase pathway in b-cell lymphoproliferative disorders. Cancer J. 22, 34–39 (2016). https://doi.org/10.1097/PPO.0000000000000170

  18. M.R. Smith, Ibrutinib in b lymphoid malignancies. Expert Opin. Pharmacother. 16, 1879–1887 (2015). https://doi.org/10.1517/14656566.2015.1067302

    Article  CAS  PubMed  Google Scholar 

  19. V. Patel, K. Balakrishnan, E. Bibikova, M. Ayres, M.J. Keating, W.G. Wierda, V. Gandhi, Comparison of acalabrutinib, a selective bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia Cells. Clin. Cancer Res. 23, 3734–3743 (2017). https://doi.org/10.1158/1078-0432.CCR-16-1446

    Article  CAS  PubMed  Google Scholar 

  20. W. Guo, R. Liu, G. Bhardwaj, J.C. Yang, C. Changou, A.H. Ma, A. Mazloom, S. Chintapalli, K. Xiao, W. Xiao, P. Kumaresan, E. Sanchez, C.T. Yeh, C.P. Evans, R. Patterson, K.S. Lam, H.J. Kung, Targeting BTK/etk of prostate cancer cells by a novel dual inhibitor. Cell. Death Dis. 5, e1409 (2014). https://doi.org/10.1038/cddis.2014.343

  21. M.A. Zucha, A.T. Wu, W.H. Lee, L.S. Wang, W.W. Lin, C.C. Yuan, C.T. Yeh, Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer. Oncotarget 6, 13255–13268 (2015). https://doi.org/10.18632/oncotarget.3658

    Article  PubMed  PubMed Central  Google Scholar 

  22. A.J. Gunderson, M.M. Kaneda, T. Tsujikawa, A.V. Nguyen, N.I. Affara, B. Ruffell, S. Gorjestani, S.M. Liudahl, M. Truitt, P. Olson, G. Kim, D. Hanahan, M.A. Tempero, B. Sheppard, B. Irving, B.Y. Chang, J.A. Varner, L.M. Coussens, Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 6, 270–285 (2016). https://doi.org/10.1158/2159-8290.CD-15-0827

    Article  CAS  PubMed  Google Scholar 

  23. L. Ping, N. Ding, Y. Shi, L. Feng, J. Li, Y. Liu, Y. Lin, C. Shi, X. Wang, Z. Pan, Y. Song, J. Zhu, The bruton’s tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages. Oncotarget 8, 39218–39229 (2017). https://doi.org/10.18632/oncotarget.16836

    Article  PubMed  PubMed Central  Google Scholar 

  24. M. Ito, T. Shichita, M. Okada, R. Komine, Y. Noguchi, A. Yoshimura, R. Morita, Bruton’s tyrosine kinase is essential for nlrp3 inflammasome activation and contributes to ischaemic brain injury. Nat. Commun. 6, 7360 (2015). https://doi.org/10.1038/ncomms8360

    Article  PubMed  PubMed Central  Google Scholar 

  25. L. Wei, Y.K. Su, C.M. Lin, T.Y. Chao, S.P. Huang, T.T. Huynh, H.J. Jan, J. Whang-Peng, J.F. Chiou, A.T. Wu, M. Hsiao, Preclinical investigation of ibrutinib, a bruton’s kinase tyrosine (BTK) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes. Oncotarget 7, 69961–69975 (2016). https://doi.org/10.18632/oncotarget.11572

  26. E.J. Yang, J.H. Yoon, K.C. Chung, Bruton’s tyrosine kinase phosphorylates camp-responsive element-binding protein at serine 133 during neuronal differentiation in immortalized hippocampal progenitor cells. J. Biol. Chem. 279, 1827–1837 (2004). https://doi.org/10.1074/jbc.M308722200

    Article  CAS  PubMed  Google Scholar 

  27. T. Li, Y. Deng, Y. Shi, R. Tian, Y. Chen, L. Zou, J.U. Kazi, L. Ronnstrand, B. Feng, S.O. Chan, W.Y. Chan, J. Sun, H. Zhao, Bruton’s tyrosine kinase potentiates alk signaling and serves as a potential therapeutic target of neuroblastoma. Oncogene 37, 6180–6194 (2018). https://doi.org/10.1038/s41388-018-0397-7

    Article  CAS  PubMed  Google Scholar 

  28. W. Allen-Rhoades, S.B. Whittle, N. Rainusso, Pediatric solid tumors of infancy: An overview. Pediatr. Rev. 39, 57–67 (2018). https://doi.org/10.1542/pir.2017-0057

    Article  PubMed  Google Scholar 

  29. V. Vichai, K. Kirtikara, Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc. 1, 1112–1116 (2006). https://doi.org/10.1038/nprot.2006.179

    Article  CAS  PubMed  Google Scholar 

  30. J. Koster, R2: Genomics Analysis and Visualization Platform http://www.r2.amc.nl. (2011)

  31. J.J. Molenaar, J. Koster, D.A. Zwijnenburg, P. van Sluis, L.J. Valentijn, I. van der Ploeg, M. Hamdi, J. van Nes, B.A. Westerman, J. van Arkel, M.E. Ebus, F. Haneveld, A. Lakeman, L. Schild, P. Molenaar, P. Stroeken, M.M. van Noesel, I. Ora, E.E. Santo, H.N. Caron, E.M. Westerhout, R. Versteeg, Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012). https://doi.org/10.1038/nature10910

    Article  CAS  PubMed  Google Scholar 

  32. J.R. Park, A. Eggert, H. Caron, Neuroblastoma: Biology, prognosis, and treatment. Hematol. Oncol. Clin. North Am. 24, 65–86 (2010). https://doi.org/10.1016/j.hoc.2009.11.011

    Article  PubMed  Google Scholar 

  33. J. Molina-Cerrillo, T. Alonso-Gordoa, P. Gajate, E. Grande, Bruton’s tyrosine kinase (BTK) as a promising target in solid tumors. Cancer Treat. Rev. 58, 41–50 (2017). https://doi.org/10.1016/j.ctrv.2017.06.001

    Article  CAS  PubMed  Google Scholar 

  34. I. Sagiv-Barfi, H.E. Kohrt, D.K. Czerwinski, P.P. Ng, B.Y. Chang, R. Levy, Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and itk. Proc. Natl. Acad. Sci. U.S.A. 112, E966–E972 (2015). https://doi.org/10.1073/pnas.1500712112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. H. Shimada, I.M. Ambros, L.P. Dehner, J. Hata, V.V. Joshi, B. Roald, D.O. Stram, R.B. Gerbing, J.N. Lukens, K.K. Matthay, R.P. Castleberry, The international neuroblastoma pathology classification (the shimada system). Cancer 86, 364–372 (1999)

    Article  CAS  Google Scholar 

  36. H.Y. Tan, N. Wang, W. Lam, W. Guo, Y. Feng, Y.C. Cheng, Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol. Cancer 17, 43 (2018). https://doi.org/10.1186/s12943-018-0800-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Y.P. Hu, Z.B. Wu, L. Jiang, Y.P. Jin, H.F. Li, Y.J. Zhang, Q. Ma, Y.Y. Ye, Z. Wang, Y.C. Liu, H.Z. Chen, Y.B. Liu, Styk1 promotes cancer cell proliferation and malignant transformation by activating pi3k-akt pathway in gallbladder carcinoma. Int. J. Biochem. Cell Biol. 97, 16–27 (2018). https://doi.org/10.1016/j.biocel.2018.01.016

    Article  CAS  PubMed  Google Scholar 

  38. W. Xu, Z. Yang, N. Lu, A new role for the pi3k/akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes. Migr. 9, 317–324 (2015). https://doi.org/10.1080/19336918.2015.1016686

    Article  CAS  Google Scholar 

  39. S.P. Singh, S.Y. Pillai, M.J.W. de Bruijn, R. Stadhouders, O.B.J. Corneth, H.J. van den Ham, A. Muggen, I.W.E. van Slinger, A. Kuil, M. Spaargaren, A.P. Kater, A.W. Langerak, R.W. Hendriks, Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive BTK and akt signaling. Oncotarget 8, 71981–71995 (2017). https://doi.org/10.18632/oncotarget.18234

    Article  PubMed  PubMed Central  Google Scholar 

  40. T.K. Moyo, C.S. Wilson, D.J. Moore, C.M. Eischen, Myc enhances b-cell receptor signaling in precancerous b cells and confers resistance to BTK inhibition. Oncogene 36, 4653–4661 (2017). https://doi.org/10.1038/onc.2017.95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Y. Yang, J. Shi, Z. Gu, M.E. Salama, S. Das, E. Wendlandt, H. Xu, J. Huang, Y. Tao, M. Hao, R. Franqui, D. Levasseur, S. Janz, G. Tricot, F. Zhan, Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res. 75, 594–604 (2015). https://doi.org/10.1158/0008-5472.CAN-14-2362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. S.K. Tripathi, Z. Chen, A. Larjo, K. Kanduri, K. Nousiainen, T. Aijo, I. Ricano-Ponce, B. Hrdlickova, S. Tuomela, E. Laajala, V. Salo, V. Kumar, C. Wijmenga, H. Lahdesmaki, R. Lahesmaa, Genome-wide analysis of stat3-mediated transcription during early human th17 cell differentiation. Cell Rep. 19, 1888–1901 (2017). https://doi.org/10.1016/j.celrep.2017.05.013

    Article  CAS  PubMed  Google Scholar 

  43. K. Hawkins, L. Mohamet, S. Ritson, C.L. Merry, C.M. Ward, E-cadherin and, in its absence, n-cadherin promotes nanog expression in mouse embryonic stem cells via stat3 phosphorylation. Stem Cells 30, 1842–1851 (2012). https://doi.org/10.1002/stem.1148

    Article  CAS  PubMed  Google Scholar 

  44. J. Hall, G. Guo, J. Wray, I. Eyres, J. Nichols, L. Grotewold, S. Morfopoulou, P. Humphreys, W. Mansfield, R. Walker, S. Tomlinson, A. Smith, Oct4 and lif/stat3 additively induce kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5, 597–609 (2009). https://doi.org/10.1016/j.stem.2009.11.003

  45. P. Zhang, R. Andrianakos, Y. Yang, C. Liu, W. Lu, Kruppel-like factor 4 (klf4) prevents embryonic stem (es) cell differentiation by regulating nanog gene expression. J. Biol. Chem. 285, 9180–9189 (2010). https://doi.org/10.1074/jbc.M109.077958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. X. Wang, J. Wong, C.J. Sevinsky, L. Kokabee, F. Khan, Y. Sun, D.S. Conklin, Bruton’s tyrosine kinase inhibitors prevent therapeutic escape in breast cancer cells. Mol. Cancer Ther. 15, 2198–2208 (2016). https://doi.org/10.1158/1535-7163.MCT-15-0813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Y. Li, N. Cui, P.S. Zheng, W.T. Yang, BMX/Etk promotes cell proliferation and tumorigenicity of cervical cancer cells through PI3K/AKT/mTOR and STAT3 pathways. Oncotarget 8, 49238–49252 (2017). https://doi.org/10.18632/oncotarget.17493

    Article  PubMed  PubMed Central  Google Scholar 

  48. J. Cidado, H.Y. Wong, D.M. Rosen, A. Cimino-Mathews, J.P. Garay, A.G. Fessler, Z.A. Rasheed, J. Hicks, R.L. Cochran, S. Croessmann, D.J. Zabransky, M. Mohseni, J.A. Beaver, D. Chu, K. Cravero, E.S. Christenson, A. Medford, A. Mattox, A.M. De Marzo, P. Argani, A. Chawla, P.J. Hurley, J. Lauring, B.H. Park, Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget 7, 6281–6293 (2016). https://doi.org/10.18632/oncotarget.7057

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the research assistants at the Core Facility Center, Department of Medical Research, Taipei Medical University - Shuang Ho Hospital, especially Mr. Iat-Hang Fong and Mr. Sam Huang, for their technical assistance with cell-based assays. The authors also thank Dr. Alexander TH Wu and Mr. Oliver Huang for their interest and constructive advice in the animal experimental designs and their skillful technical support of this project. This manuscript was edited by Wallace Academic Editing.

Funding

This work was supported by the National Science Council of Taiwan: Tsu-Yi Chao (MOST105-2314-B038-080 and MOST 108-2314-B-038-051-MY3). It was also supported by a grant from National Taiwan University Hospital: Wen-Ming Hsu (107-S3825).

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Authors and Affiliations

  1. International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, 110, Taipei City, Taiwan

    Narpati Wesa Pikatan, Tsu-Yi Chao & Chi-Tai Yeh

  2. Doctorate Program of Medical and Health Science, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, 55281, Yogyakarta, Indonesia

    Narpati Wesa Pikatan

  3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 110, Taipei City, Taiwan

    Narpati Wesa Pikatan, Tsu-Yi Chao & Chi-Tai Yeh

  4. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, 110, Taipei City, Taiwan

    Yen-Lin Liu

  5. Department of Pediatrics, Taipei Medical University Hospital, 110, Taipei City, Taiwan

    Yen-Lin Liu

  6. Taipei Cancer Center, Taipei Medical University, 110, Taipei City, Taiwan

    Yen-Lin Liu & Tsu-Yi Chao

  7. Department of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital, 235, New Taipei City, Taiwan

    Oluwaseun Adebayo Bamodu, Tsu-Yi Chao & Chi-Tai Yeh

  8. Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, 235, New Taipei City, Taiwan

    Oluwaseun Adebayo Bamodu, Tsu-Yi Chao & Chi-Tai Yeh

  9. Genomics Research Center, Academia Sinica, 11529, Taipei City, Taiwan

    Michael Hsiao

  10. Department of Surgery, National Taiwan University Hospital, 100, Taipei City, Taiwan

    Wen-Ming Hsu

  11. Department of Histology and Cellular Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, 55281, Yogyakarta, Indonesia

    Sofia Mubarika Haryana

  12. Department of Pediatrics, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, 55281, Yogyakarta, Indonesia

    Sutaryo

  13. Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, 30015, Hsinchu City, Taiwan

    Chi-Tai Yeh

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  1. Narpati Wesa Pikatan
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Contributions

NWP: project conception, experimental design, generation and collation of data, data analysis and interpretation, manuscript writing. YLL, OAB: project conception, experimental design, collation and/or assembly of data, data analysis and interpretation, manuscript writing and revision. YLL, MH, WMH: data assembly and analysis. SMH and Sutaryo: assistance with data generation. MH, CTY, TYC: experimental design, data analysis and interpretation, provision of useful research insight and essential reagents, and administrative oversight. All authors read and approved the final submitted version.

Corresponding authors

Correspondence to Tsu-Yi Chao or Chi-Tai Yeh.

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Ethics approval and consent to participate

Clinical samples were collected from the National Taiwan University Hospital (Taipei City, Taiwan). All enrolled patients gave written informed consent for their tissues to be used for scientific research. The study was approved by the Joint Institutional Review Board of National Taiwan University Hospital (201705121RIND), consistent with the recommendations of the Declaration of Helsinki for biomedical research.

Conflict of interest

The authors have declared no conflicts of interest. The authors declare that they have no potential financial competing interests that may in any way gain or lose financially from the publication of this manuscript at present or in the future. Additionally, no nonfinancial competing interests are involved in the manuscript.

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Highlights

• Bruton’s Tyrosine Kinase (BTK) is highly expressed in neuroblastoma

• High BTK expressing tumors is associated with poorer prognosis

• BTK inhibitor, Ibrutinib, reduced neuroblastoma cells migration and invasion ability

• Ibrutinib also lowered Neuro-sphere formation potential of neuroblastoma cells

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Pikatan, N.W., Liu, YL., Bamodu, O.A. et al. Aberrantly expressed Bruton’s tyrosine kinase preferentially drives metastatic and stem cell-like phenotypes in neuroblastoma cells. Cell Oncol. 43, 1067–1084 (2020). https://doi.org/10.1007/s13402-020-00541-5

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  • DOI: https://doi.org/10.1007/s13402-020-00541-5

Keywords

  • Pediatric brain tumor
  • Neuroblastoma
  • Bruton’s tyrosine kinase
  • Ibrutinib
  • Acalabrutinib
  • Cancer stem cells
  • Metastasis