Krauss Theresa, Gürcinar Ibrahim Halil, Bourquain Ulrike, Hieber Maren, Krohmer Evelyn N, Wu Nan, Tokalov Sergey, Goess Rüdiger, Reyes Carmen Mota, Saur Dieter, Friess Helmut, Ceyhan Güralp O, Demir Ihsan Ekin, Safak Okan
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, Germany.
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
Neoplasia. 2025 Feb;60:101126. doi: 10.1016/j.neo.2025.101126. Epub 2025 Jan 21.
Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (Ptf1a, LSL-Kras, LSL-R26), decreased perineural integrity could be reproduced in vivo.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion.
神经侵犯是胰腺导管腺癌（PDAC）的一个预后标志，但神经周围屏障破坏以及癌细胞进入胰腺内神经的潜在机制仍知之甚少。本研究旨在探讨上皮-间质转化（EMT）在神经侵犯过程中对神经周围上皮细胞的作用。使用神经束膜特异性GLUT1抗体对人和小鼠原发性肿瘤进行组织病理学分析，结果显示神经周围完整性降低，这与人类PDAC病例中的神经侵犯程度呈正相关。研究发现，人胰腺癌细胞系分泌TGFβ1，可诱导神经周围上皮细胞发生EMT，其特征为上皮标志物（CK19-9）丢失和间充质标志物（αSMA、N-钙黏蛋白）获得。此外，这些正在转变的神经周围上皮细胞通过SMAD2上调基质金属蛋白酶3和9，表现出增强的基质降解能力。在一个除致癌性Kras激活（Ptf1a、LSL-Kras、LSL-R26）外内源性TGFβ1水平升高的原位小鼠模型中，可在体内重现神经周围完整性降低的情况。总体而言，这些发现强调了TGFβ1过表达的胰腺癌细胞在神经侵犯过程中破坏神经周围屏障所起的作用。
