Mutation spectrum and pathway signatures mark neuroblastoma cells reflecting multiple developmental stages

      Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system, which is a neural crest derived lineage. We study intra-tumoral heterogeneity of neuroblastoma and identified two major cell types. We can culture both types in vitro using defined neural stem cell medium. One type is mesenchymal and shows a high motility, while the other type characterizes as neuro-epithelial (NE) and expresses more mature differentiation markers. The two cell types differ in activation of many molecular pathways. Immunohistochemical analysis shows that all neuroblastoma tumors include both cell types in vivo. Both cell types can in vitro spontaneously transdifferentiate into each other. We identified several genes and pathways that can induce this transition. We have also sequenced the full genomes of >100 neuroblastoma tumors and thus identified the full mutation spectrum of genes in this tumor. Remarkably, some recurrently mutated genes relate to pathways and functions controlling the transition between mesenchymal and neuro-epithelial cell types. We assume that both phenotypic appearances of neuroblastoma reflect normal differentiation stages of neuroblasts, especially a motile stage of undifferentiated cells and the more differentiated stages producing catecholamines. As tumor heterogeneity, EMT and stemness are highly relevant for metastasis and drug resistance, the study of pathway and mutations underlying these processes has clinical implications.
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