A metastatic mouse model identifies genes that regulate neuroblastoma metastasis

Metastatic relapse is the major cause of death in pediatric neuroblastoma (NB), where there remains a lack of therapies to target this stage of disease. To understand the molecular mechanisms mediating NB 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 412 genes and 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 NB 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, pharmcological targeting of SPHK1 or YAP/TAZ was sufficient to inhibit NB metastasis in vivo. Overall, our findings defined gene expression signatures and candidate therapeutics that could improve the treatment of metastatic NB.

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