周围神经系统是癌症进展的关键调节因子。在胰腺导管腺癌（PDAC）中，自主神经系统的交感神经分支抑制癌症的发展。这种抑制与早期胰腺癌前驱病变中广泛的交感神经萌芽有关。然而，这一过程背后的潜在机制仍不清楚。本研究旨在探讨胰腺雪旺细胞在交感神经元结构可塑性中的作用。我们检查了 PDAC 转基因小鼠模型和慢性炎症诱导的化生性胰腺病变模型中雪旺细胞数量和分布的变化。在化生性/肿瘤性胰腺病变中，雪旺细胞与新的交感神经芽同时增殖和扩张。稀疏的基因标记表明，这些病变中的单个雪旺细胞比生理条件下的雪旺细胞具有更细长和分支的结构。雪旺细胞过度表达神经营养因子，包括胶质细胞源性神经营养因子（GDNF）。在体外，交感神经元对 GDNF 受体上调，并表现出对 GDNF 反应增强的神经突生长。雪旺细胞中 Gdnf 的选择性基因删除完全阻断了体内化生性胰腺病变中交感神经的萌发。这项研究表明，胰腺雪旺细胞在早期癌症发展过程中经历了适应性重编程，支持保护性抗肿瘤神经元反应。这些发现可能有助于开发新的策略来调节癌症相关的神经可塑性。© 2024 作者。 GLIA 由 Wiley periodicals LLC 出版。

The peripheral nervous system is a key regulator of cancer progression. In pancreatic ductal adenocarcinoma (PDAC), the sympathetic branch of the autonomic nervous system inhibits cancer development. This inhibition is associated with extensive sympathetic nerve sprouting in early pancreatic cancer precursor lesions. However, the underlying mechanisms behind this process remain unclear. This study aimed to investigate the roles of pancreatic Schwann cells in the structural plasticity of sympathetic neurons. We examined the changes in the number and distribution of Schwann cells in a transgenic mouse model of PDAC and in a model of metaplastic pancreatic lesions induced by chronic inflammation. Schwann cells proliferated and expanded simultaneously with new sympathetic nerve sprouts in metaplastic/neoplastic pancreatic lesions. Sparse genetic labeling showed that individual Schwann cells in these lesions had a more elongated and branched structure than those under physiological conditions. Schwann cells overexpressed neurotrophic factors, including glial cell-derived neurotrophic factor (GDNF). Sympathetic neurons upregulated the GDNF receptors and exhibited enhanced neurite growth in response to GDNF in vitro. Selective genetic deletion of Gdnf in Schwann cells completely blocked sympathetic nerve sprouting in metaplastic pancreatic lesions in vivo. This study demonstrated that pancreatic Schwann cells underwent adaptive reprogramming during early cancer development, supporting a protective antitumor neuronal response. These finding could help to develop new strategies to modulate cancer associated neural plasticity.© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.