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

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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.

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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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