Huang Yue, Tsubota Shoma, Nishio Nobuhiro, Takahashi Yoshiyuki, Kadomatsu Kenji
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Sci. 2021 Feb;112(2):715-724. doi: 10.1111/cas.14760. Epub 2020 Dec 21.
Neuroblastoma, a type of cancer that is common in children, is composed of two genetically clonal but epigenetically distinct cell types: mesenchymal (MES) and adrenergic (ADRN) types, controlled by super-enhancer-associated lineage-specific transcription factor networks. Mesenchymal-type cells are more migratory, resistant to chemotherapy, and prevalent in relapse tumors. Importantly, both cell types spontaneously transdifferentiate into one another, and this interconversion can be induced by genetic manipulations. However, the mechanisms of their spontaneous transdifferentiation and extracellular factors inducing this phenomenon have not yet been elucidated. Using a unique approach involving gene set enrichment analysis, we selected six ADRN and 10 MES candidate factors, possibly inducing ADRN and MES phenotypes, respectively. Treatment with a combination of 10 MES factors clearly induced the MES gene expression profile in ADRN-type SH-SY5Y neuroblastoma cells. Considering the effects on gene expression profile, migration ability, and chemoresistance, a combination of tumor necrosis factor alpha (TNF-α) and epidermal growth factor (EGF) was sufficient to synergistically induce the ADRN-to-MES transdifferentiation in SH-SY5Y cells. In addition, human neuroblastoma cohort analysis revealed that the expression of TNF and EGF receptors was strongly associated with MES gene expression signatures, supporting their important roles in transdifferentiation in vivo. Collectively, we propose a mechanism of neuroblastoma transdifferentiation induced by extracellular growth factors, which can be controlled in clinical situations, providing a new therapeutic possibility.
神经母细胞瘤是一种常见于儿童的癌症，由两种基因克隆但表观遗传不同的细胞类型组成：间充质（MES）型和肾上腺素能（ADRN）型，受超级增强子相关的谱系特异性转录因子网络控制。间充质型细胞迁移性更强，对化疗有抗性，且在复发性肿瘤中普遍存在。重要的是，这两种细胞类型会自发地相互转分化，并且这种相互转化可以通过基因操作来诱导。然而，它们自发转分化的机制以及诱导这种现象的细胞外因子尚未阐明。我们采用一种独特的方法，涉及基因集富集分析，分别选择了六个可能诱导ADRN表型和十个可能诱导MES表型的ADRN和MES候选因子。用10个MES因子的组合处理明显诱导了ADRN型SH-SY5Y神经母细胞瘤细胞中的MES基因表达谱。考虑到对基因表达谱、迁移能力和化疗抗性的影响，肿瘤坏死因子α（TNF-α）和表皮生长因子（EGF）的组合足以协同诱导SH-SY5Y细胞中ADRN向MES的转分化。此外，人类神经母细胞瘤队列分析显示，TNF和EGF受体的表达与MES基因表达特征密切相关，支持它们在体内转分化中的重要作用。总的来说，我们提出了一种由细胞外生长因子诱导的神经母细胞瘤转分化机制，这种机制在临床情况下可以得到控制，提供了一种新的治疗可能性。
