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Cancer Res. 2017 Feb 1;77(3):696-706. doi: 10.1158/0008-5472.CAN-16-1502. Epub 2016 Nov 29.

A Metastatic Mouse Model Identifies Genes That Regulate Neuroblastoma Metastasis.

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
2
Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
3
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
4
Informatics and Bio-computing, Ontario Institute of Cancer Research, Toronto, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
6
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
7
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. meredith.irwin@sickkids.ca dkaplan@sickkids.ca.
8
Department of Paediatrics, University of Toronto, Toronto, Canada.
9
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada. meredith.irwin@sickkids.ca dkaplan@sickkids.ca.

Abstract

Metastatic relapse is the major cause of death in pediatric neuroblastoma, where there remains a lack of therapies to target this stage of disease. To understand the molecular mechanisms mediating neuroblastoma metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate malignant cell subpopulations with a higher propensity for metastasis to bone and the central nervous system. Gene expression profiling revealed primary and metastatic cells as two distinct cell populations defined by differential expression of 412 genes and of multiple pathways, including CADM1, SPHK1, and YAP/TAZ, whose expression independently predicted survival. In the metastatic subpopulations, a gene signature was defined (MET-75) that predicted survival of neuroblastoma patients with metastatic disease. Mechanistic investigations demonstrated causal roles for CADM1, SPHK1, and YAP/TAZ in mediating metastatic phenotypes in vitro and in vivo Notably, pharmacologic targeting of SPHK1 or YAP/TAZ was sufficient to inhibit neuroblastoma metastasis in vivo Overall, we identify gene expression signatures and candidate therapeutics that could improve the treatment of metastatic neuroblastoma. Cancer Res; 77(3); 696-706.

PMID:
27899382
DOI:
10.1158/0008-5472.CAN-16-1502
[Indexed for MEDLINE]
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