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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Publication history
Received:
May 15,
2013
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Copyright
© 2013 Published by Elsevier Inc.