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.
Highlights
Neuroblastoma is the most common extra-cranial solid tumor and most frequent cause of cancer-related death in children [1]
The human neuroblastoma cell line SK-N-AS was infected with a retrovirus encoding a triple reporter (TR) consisting of thymidine kinase, GFP, and luciferease, which allows for nuclear imaging, FACS analysis, and whole body bioluminescence, respectively [15]
We focused on sphingosine kinase 1 (SPHK1), which catalyzes the phosphorylation of sphingosine to generate the lipid second messenger sphingosine-1-phosphate (S1P), as a candidate since SPHK1 is located on a region of chromosome 17q that is frequently amplified in neuroblastoma and predicts poor outcome [35]
Summary
Neuroblastoma is the most common extra-cranial solid tumor and most frequent cause of cancer-related death in children [1]. Neuroblastoma is of neural crest origin and most often arises in the adrenal gland, more than half of patients present with distant metastases, and less than 40% are long-term survivors. The majority of patients have evidence of metastatic spread to the bones, bone marrow, and increasingly, the central nervous system There has been significant progress in the identification of genetic alterations in primary neuroblastoma tumors, including MYCN amplification and mutations in genes such as ALK and ATRX [4,5,6,7], recurrent driver mutations are. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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