Schwann cell plasticity regulates neuroblastic tumor cell differentiation - phosphoproteomics

The remarkable plasticity of Schwann cells (SCs) is essential for nerve regeneration but also contributes to neuropathies and cancer progression. It has not yet been investigated whether the adaptive potential of SCs is manifested in stromal, tumor associated SCs characteristically found within a benign subtype of neuroblastic tumors (NBTs). We here performed transcriptome profiling of human NBTs, rich and poor in SC stroma, as well as human injured nerves, rich in repair SCs, revealing that stromal SCs exhibit a repair SC characteristic gene expression signature. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on NBT cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of aggressive NBT cells. EGFL8 expression further correlated with favorable tumor stage and increased patient survival. Our findings suggest that stromal SCs exert nerve repair associated functions in the tumor-environment and underline the therapeutic value of SC-derived factors for aggressive, SC stroma-poor NBTs.

雪旺细胞（Schwann cells, SCs）显著的可塑性不仅对神经再生至关重要，同时也参与神经病变及癌症进展过程。目前尚未有研究探讨雪旺细胞的适应潜能是否会在良性神经母细胞瘤样肿瘤（neuroblastic tumors, NBTs）亚型中特征性存在的肿瘤相关基质雪旺细胞中得以体现。本研究对富含与缺乏雪旺细胞基质的人类神经母细胞瘤样肿瘤，以及富含修复型雪旺细胞的人类损伤神经开展了转录组分析，结果显示基质雪旺细胞呈现出修复型雪旺细胞特征性的基因表达谱。进一步的直接共培养及跨室共培养实验表明，原代修复型雪旺细胞对神经母细胞瘤样肿瘤细胞系具有促分化及抗增殖作用。在分泌型基质/修复型雪旺细胞因子库中，本研究鉴定出EGFL8——一种目前功能尚未阐明的基质细胞蛋白——可诱导侵袭性神经母细胞瘤样肿瘤细胞发生神经元分化。EGFL8的表达水平还与良好的肿瘤分期及更长的患者生存期呈正相关。本研究结果表明，基质雪旺细胞在肿瘤微环境中发挥神经修复相关功能，同时也凸显了雪旺细胞来源的因子在治疗侵袭性、缺乏雪旺细胞基质的神经母细胞瘤样肿瘤中的应用价值。