Abstract
Neuroblastoma (NB) is the most common cancer in infants and it accounts for six percent of all pediatric malignancies. There are several hypotheses proposed on the origins of NB. While there is little genetic evidence to support this, the prevailing model is that NB originates from neural crest stem cells (NCSCs). Utilizing in vivo mouse models, we demonstrate that targeting MYCN oncogene to NCSCs causes perinatal lethality. During sympathoadrenal (SA) lineage development, SOX transcriptional factors drive the transition from NCSCs to lineage-specific progenitors, characterized by the sequential activation of Sox9/Sox10/Sox4/Sox11 genes. We find the NCSCs factor SOX10 is not expressed in neuroblasts, but rather restricted to the Schwannian stroma and is associated with a good prognosis. On the other hand, SOX9 expression in NB cells was associated with several key biological processes including migration, invasion and differentiation. Moreover, manipulating SOX9 gene predominantly affects lineage-restricted SA progenitors. Our findings highlight a unique molecular SOX signature associated with NB that is highly reminiscent of SA progenitor transcriptional program during embryonic development, providing novel insights into NB pathobiology. In summary, we provide multiple lines of evidence suggesting that multipotent NCSCs do not contribute to NB initiation and maintenance.
Highlights
Neuroblastoma (NB) is a pediatric malignancy affecting infants and young children with median age at diagnosis is 17 months [1]
Since MYCN amplification is the most common genetic aberration in sporadic NB and occurs in approximately 25 percent of tumors [2], we used LSL-MYCN mice, a genetically engineered mouse model in which MYCN oncogene is activated upon Cremediated recombination [14]
Based on our breeding scheme, we expected that 100% of resulting offspring should be hemizygous for LSL-MYCN allele, and 50% should inherit Cre transgene resulting in approximately 50% of pups carrying both transgenes
Summary
Neuroblastoma (NB) is a pediatric malignancy affecting infants and young children with median age at diagnosis is 17 months [1]. The remarkable clinical and biological diversity of NB can vary from patient to patient and one of the hallmarks of NB is its unique capacity to undergo spontaneous regression [5] Such composite nature of NB cannot be explained genetically since high-throughput sequencing uncovered low mutational burden in primary NB [6]. Several recent studies presented convincing evidence that in vitro NCSCs can act as a cellular population capable of NB initiation, when transduced with MYCN, ALKF1174L and ALKR1275Q oncogenes and injected into immunocompromised mice [7,8,9] These findings and other notable parallels shared by NCSCs and NB cells, including remarkable capacity to metastasize, have led to a number of recent reviews proposing NCSCs as the cell-of-origin and CSCs in NB [10,11,12,13]. No functional evidence has been obtained for the presence of NCSCs in human patient’s biopsies
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