title: A Metastatic Mouse Model Identifies Genes That Regulate Neuroblastoma Metastasis.
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. ©2017 AACR.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Bo Kyung A
authors.initials: BK
authors.lastname: Seong
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Fathers
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Hallett
authors.affiliation: Informatics and Bio-computing, Ontario Institute of Cancer Research, Toronto, Canada.
authors.forename: Christina K
authors.initials: CK
authors.lastname: Yung
authors.affiliation: Informatics and Bio-computing, Ontario Institute of Cancer Research, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Samar
authors.initials: S
authors.lastname: Mouaaz
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Lynn
authors.initials: L
authors.lastname: Kee
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Hawkins
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. meredith.irwin@sickkids.ca dkaplan@sickkids.ca.|Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.|Department of Paediatrics, University of Toronto, Toronto, Canada.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada. meredith.irwin@sickkids.ca dkaplan@sickkids.ca.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D064593:Heterografts; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome; D055114:X-Ray Microtomography