Wong Fang Cheng, Merker Sebastian R, Bauer Lisa, Han Yi, Le Van Manh Hung, Wenzel Carina, Böthig Lukas, Heiduk Max, Drobisch Pascal, Rao Venkatesh Sadananda, Malekian Farzaneh, Mansourkiaei Ana, Sperling Christian, Polster Heike, Pecqueux Mathieu, Istvanffy Rouzanna, Ye Linhan, Kong Bo, Aust Daniela E, Baretton Gustavo, Seifert Lena, Seifert Adrian M, Weitz Jürgen, Demir Ihsan Ekin, Kahlert Christoph
Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT/UCC), Dresden, Germany.
Br J Cancer. 2025 Mar;132(4):326-339. doi: 10.1038/s41416-024-02915-0. Epub 2025 Jan 25.
Pancreatic ductal adenocarcinoma (PDAC) exhibits a high frequency of neural invasion (NI). Schwann cells (SCs) have been shown to be reprogrammed to facilitate cancer cell migration and invasion into nerves. Since extracellular vesicles (EVs) affect the tumour microenvironment and promote metastasis, the present study analysed the involvement of EVs from pancreatic cancer cells and their microenvironment in altering SC phenotype as part of the early events in the process of NI.
EVs were isolated from human/murine PDAC cells, pancreatic stellate cells (PSCs), human tissues and plasma to perform a novel 3D migration assay, qRT-PCR and western blot. Kaplan-Meier and Cox regression analyses were employed to evaluate the clinical potential of plasma EV-derived candidate from 165 PDAC patients.
The EVs from PDAC cells, PSCs derived from human tumour tissues, other cell types in the tumour microenvironment from tumour tissues and circulating plasma act as drivers of a pro-migratory phenotype of SCs by inducing dedifferentiation in SCs. Notably, p75NTR expression was upregulated in the plasma-derived EVs from patients with NI (Pn1) relative to those without NI (Pn0). High expression of plasma-derived EV p75NTR correlated with reduced overall survival and was identified as an independent prognostic factor.
These findings suggest that EV-mediated SC migration underlies the interactions contributing to PDAC-associated NI with implications for improved outcome and therapeutic strategy.
胰腺导管腺癌（PDAC）具有较高的神经侵犯（NI）发生率。已表明雪旺细胞（SCs）会发生重编程以促进癌细胞迁移并侵入神经。由于细胞外囊泡（EVs）会影响肿瘤微环境并促进转移，因此本研究分析了胰腺癌细胞及其微环境来源的EVs在改变SCs表型中的作用，这是NI过程早期事件的一部分。
从人/鼠PDAC细胞、胰腺星状细胞（PSCs）、人体组织和血浆中分离出EVs，以进行新型三维迁移试验、qRT-PCR和蛋白质免疫印迹。采用Kaplan-Meier和Cox回归分析来评估165例PDAC患者血浆EVs衍生候选物的临床潜力。
来自PDAC细胞、源自人肿瘤组织的PSCs、肿瘤组织肿瘤微环境中的其他细胞类型以及循环血浆的EVs，通过诱导SCs去分化，成为SCs促迁移表型的驱动因素。值得注意的是，与无NI患者（Pn0）相比，有NI患者（Pn1）血浆来源的EVs中p75NTR表达上调。血浆来源的EV p75NTR高表达与总生存期缩短相关，并被确定为独立的预后因素。
这些发现表明，EV介导的SCs迁移是导致PDAC相关NI的相互作用的基础，对改善预后和治疗策略具有重要意义。
