ALK R1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN

T. Ueda, Y. Nakata, N. Yamasaki, H. Oda, K. Sentani, A. Kanai, N. Onishi, K. Ikeda, Y. Sera, Z. I. Honda, K. Tanaka, M. Sata, S. Ogawa, W. Yasui, Hideyuki Saya, J. Takita, H. Honda

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14 Citations (Scopus)

Abstract

Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK R1275Q, an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK R1275Q knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK R1275Q globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK R1275Q /MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK R1275Q -expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK R1275Q /MYCN mice. These results collectively indicate that ALK R1275Q confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK R1275Q /MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK R1275Q -positive tumors.

Original languageEnglish
Pages (from-to)4447-4458
Number of pages12
JournalOncogene
Volume35
Issue number34
DOIs
Publication statusPublished - 2016 Aug 25

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ueda, T., Nakata, Y., Yamasaki, N., Oda, H., Sentani, K., Kanai, A., Onishi, N., Ikeda, K., Sera, Y., Honda, Z. I., Tanaka, K., Sata, M., Ogawa, S., Yasui, W., Saya, H., Takita, J., & Honda, H. (2016). ALK R1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN. Oncogene, 35(34), 4447-4458. https://doi.org/10.1038/onc.2015.519