神经周围侵犯（PNI）是胰腺导管腺癌（PDAC）的不良预后特征。然而，对肿瘤微环境中肿瘤与神经信号之间相互作用的理解是有限的。在本研究中，我们发现MUC21是PDAC预后不良的独立危险因素。此外，我们证明MUC21通过激活JNK和诱导上皮间质转化（EMT）来促进PDAC细胞的转移和PNI。从机制上讲，雪旺细胞分泌的胶质细胞源性神经营养因子通过 PDAC 细胞中的 CDK1 磷酸化 MUC21 的胞内结构域 S543，促进 MUC21 和 RAC2 之间的相互作用。这种相互作用导致 RAC2 的膜锚定和激活，进而激活 JNK/ZEB1/EMT 轴，最终增强 PDAC 细胞的转移和 PNI。我们的结果提出了 PNI 的一种新机制，表明 MUC21 是 PDAC 的潜在预后标志物和治疗靶点。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.