Cave Donatella Delle, Di Domenico Annalisa, Fantuz Marco, Ciotola Marianna, Mangini Maria, Buonaiuto Silvia, Corrado Brunella, Corona Marco, Saracino Federica, Andolfi Gennaro, Di Biase Ilaria, Cucciardi Antonio, Carrer Alessandro, Sainz Bruno, Pirozzi Teresa, Re Daniele Lo, Colonna Vincenza, Minchiotti Gabriella, De Luca Anna Chiara, Lonardo Enza
Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (IGB), CNR, Naples, Italy.
Department of Biology, University of Padova, Padova, Italy.
Cell Death Dis. 2025 Aug 6;16(1):592. doi: 10.1038/s41419-025-07859-8.
The highly fibrotic microenvironment of pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, particularly in drug delivery and tumor progression. Our study investigates the role of collagen dynamics in PDAC, revealing that TGF-β1 negatively regulates the expression of L1 cell adhesion molecule (L1CAM), leading to a more invasive tumor phenotype. We identify a subset of PDAC cells with low L1CAM expression (L1) that actively influences collagen deposition and remodeling, as evidenced by the upregulation of collagen 17A1 (COL17A1) and matrix metalloproteinase 2 (MMP2), both associated with poor prognosis. In vivo studies demonstrate that L1 cells correlate with increased collagen deposition, reduced sensitivity to gemcitabine, and heightened liver metastasis. The secretion of COL17A1 and MMP2 by these cells enhances their migratory capabilities and contributes to the formation of a fibrotic stroma that facilitates tumor progression. This interaction underscores the critical role of collagen in shaping the tumor microenvironment and promoting aggressive tumor behavior. Notably, treatment with Tranilast significantly reduced collagen deposition and MMP2 levels while promoting L1CAM expression, suggesting a therapeutic avenue for counteracting the aggressive characteristics of L1 cells. By modulating collagen dynamics and enhancing drug delivery, Tranilast may improve treatment outcomes for patients with low L1CAM-expressing tumors. Understanding the mechanisms by which L1 cells contribute to collagen secretion and tumor aggressiveness is essential for developing effective interventions in pancreatic cancer.
胰腺导管腺癌（PDAC）高度纤维化的微环境给有效治疗带来了重大挑战，尤其是在药物递送和肿瘤进展方面。我们的研究调查了胶原蛋白动态变化在PDAC中的作用，发现转化生长因子-β1（TGF-β1）负向调节L1细胞粘附分子（L1CAM）的表达，导致肿瘤表型更具侵袭性。我们鉴定出一组L1CAM表达较低的PDAC细胞（L1），它们积极影响胶原蛋白的沉积和重塑，胶原蛋白17A1（COL17A1）和基质金属蛋白酶2（MMP2）的上调证明了这一点，这两者都与预后不良相关。体内研究表明，L1细胞与胶原蛋白沉积增加、对吉西他滨敏感性降低以及肝转移增加有关。这些细胞分泌的COL17A1和MMP2增强了它们的迁移能力，并有助于形成促进肿瘤进展的纤维化基质。这种相互作用强调了胶原蛋白在塑造肿瘤微环境和促进肿瘤侵袭行为中的关键作用。值得注意的是，曲尼司特治疗显著减少了胶原蛋白沉积和MMP2水平，同时促进了L1CAM表达，这表明了一条对抗L1细胞侵袭性特征的治疗途径。通过调节胶原蛋白动态变化和增强药物递送，曲尼司特可能改善低L1CAM表达肿瘤患者的治疗效果。了解L1细胞促进胶原蛋白分泌和肿瘤侵袭性的机制对于开发有效的胰腺癌干预措施至关重要。
