title: ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
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.
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakata
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamasaki
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Oda
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sentani
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-kui, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Onishi
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sera
authors.affiliation: Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo, Japan.
authors.forename: Z-I
authors.initials: ZI
authors.lastname: Honda
authors.affiliation: Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramotocho, Tokushima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sata
authors.affiliation: Department of Pathology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-kui, Tokyo, Japan.
authors.forename: H
authors.identifier: 0000-0001-6610-1902
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Takita
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Honda
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000077547:Crizotinib; D005109:Extracellular Matrix / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology
chemical_list: D000071447:N-Myc Proto-Oncogene Protein; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
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