Yang Chia-Lung, Serra-Roma André, Gualandi Marco, Bodmer Nicole, Niggli Felix, Schulte Johannes Hubertus, Bode Peter Karl, Shakhova Olga
Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.
Department of Oncology, Children Hospital of Zürich, Zürich, Switzerland.
Oncotarget. 2020 Jun 16;11(24):2357-2371. doi: 10.18632/oncotarget.27636.
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 mouse models, we demonstrate that targeting 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 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 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.
神经母细胞瘤（NB）是婴儿中最常见的癌症，占所有儿童恶性肿瘤的6%。关于NB的起源提出了几种假说。虽然几乎没有遗传证据支持这一点，但普遍的模型是NB起源于神经嵴干细胞（NCSCs）。利用小鼠模型，我们证明将致癌基因靶向NCSCs会导致围产期死亡。在交感肾上腺（SA）谱系发育过程中，SOX转录因子驱动从NCSCs到谱系特异性祖细胞的转变，其特征是基因的顺序激活。我们发现NCSCs因子SOX10在神经母细胞中不表达，而是局限于施万细胞基质，并且与良好的预后相关。另一方面，NB细胞中SOX9的表达与包括迁移、侵袭和分化在内的几个关键生物学过程相关。此外，操纵基因主要影响谱系受限的SA祖细胞。我们的研究结果突出了与NB相关的独特分子SOX特征，这与胚胎发育过程中的SA祖细胞转录程序高度相似，为NB病理生物学提供了新的见解。总之，我们提供了多条证据表明多能NCSCs对NB的起始和维持没有贡献。
