RRC ID 39788
Author Ueda T, Nakata Y, Yamasaki N, Oda H, Sentani K, Kanai A, Onishi N, Ikeda K, Sera Y, Honda ZI, Tanaka K, Sata M, Ogawa S, Yasui W, Saya H, Takita J, Honda H.
Title ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
Journal Oncogene
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.
Volume 35(34)
Pages 4447-58
Published 2016-8-25
DOI 10.1038/onc.2015.519
PII onc2015519
PMID 26829053
MeSH Anaplastic Lymphoma Kinase Animals Crizotinib Extracellular Matrix / metabolism* Mice Mice, Inbred C57BL Mutation* N-Myc Proto-Oncogene Protein / genetics* Neoplasm Invasiveness Neuroblastoma / drug therapy Neuroblastoma / etiology* Neuroblastoma / genetics Neuroblastoma / pathology Pyrazoles / therapeutic use Pyridines / therapeutic use Receptor Protein-Tyrosine Kinases / antagonists & inhibitors Receptor Protein-Tyrosine Kinases / genetics* Receptor Protein-Tyrosine Kinases / physiology
IF 7.971
Times Cited 14
Mice RBRC01828