GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma
Open Access
- 18 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (11), 2995-3007
- https://doi.org/10.1158/0008-5472.can-20-1890
Abstract
One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression. Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. See related commentary by Menard, p. 2815Other Versions
Funding Information
- National Cancer Institute (R01 CA240323)
- V Foundation for Cancer Research (D2018-005)
- NCI (R01 CA1247709, R01 CA180692, R35 CA220500)
This publication has 51 references indexed in Scilit:
- Activated ALK Collaborates with MYCN in Neuroblastoma PathogenesisCancer Cell, 2012
- A model 450 million years in the making: zebrafish and vertebrate immunityDisease Models & Mechanisms, 2012
- Epigenomic Analysis of Aberrantly Methylated Genes in Colorectal Cancer Identifies Genes Commonly Affected by Epigenetic AlterationsAnnals of Surgical Oncology, 2011
- Integrative genomics identifies LMO1 as a neuroblastoma oncogeneNature, 2010
- Outcome after Reduced Chemotherapy for Intermediate-Risk NeuroblastomaThe New England Journal of Medicine, 2010
- Recent Advances in NeuroblastomaThe New England Journal of Medicine, 2010
- High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed NeuroblastomaClinical Cancer Research, 2010
- Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPsRNA, 2008
- Structural Basis of Membrane Invagination by F-BAR DomainsCell, 2008
- Stages of embryonic development of the zebrafishDevelopmental Dynamics, 1995