Ferrara Benedetta, Bourgoin-Voillard Sandrine, Habert Damien, Vallée Benoit, Nicolas-Boluda Alba, Simanic Isidora, Seve Michel, Vingert Benoit, Gazeau Florence, Castellano Flavia, Cohen José, Courty José, Cascone Ilaria
Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Proteomics. 2024 Dec;24(23-24):e2400058. doi: 10.1002/pmic.202400058. Epub 2024 Sep 16.
The fibrotic stroma characterizing pancreatic ductal adenocarcinoma (PDAC) derives from a progressive tissue rigidification, which induces epithelial mesenchymal transition and metastatic dissemination. The aim of this study was to investigate the influence of matrix stiffness on PDAC progression by analyzing the proteome of PDAC-derived extracellular vesicles (EVs). PDAC cell lines (mPDAC and KPC) were grown on synthetic supports with a stiffness close to non-tumor (NT) or tumor tissue (T), and the protein expression levels in cell-derived EVs were analyzed by a quantitative MS label-free mass spectrometry approach. Our analysis figured out 15 differentially expressed proteins (DEPs) in mPDAC-EVs and 20 DEPs in KPC-EVs in response to matrix rigidification. Up-regulated proteins participate to the processes of metabolism, matrix remodeling, and immune response, altogether hallmarks of PDAC progression. A multimodal network analysis revealed that the majority of DEPs are strongly related to pancreatic cancer. Interestingly, among DEPs, 11 related genes (ACTB/ANXA7/C3/IGSF8/LAMC1/LGALS3/PCD6IP/SFN/TPM3/VARS/YWHAZ) for mPDAC-EVs and 9 (ACTB/ALDH2/GAPDH/HNRNPA2B/ITGA2/NEXN/PKM/RPN1/S100A6) for KPC-EVs were significantly overexpressed in tumor tissues according to gene expression profiling interaction analysis (GEPIA). Concerning the potential clinical relevance of these data, the cluster of ACTB, ITGA2, GAPDH and PKM genes displayed an adverse effect (p < 0.05) on the overall survival of PDAC patients.
胰腺导管腺癌（PDAC）的特征性纤维化基质源于进行性组织硬化，这种硬化会诱导上皮-间质转化和转移扩散。本研究的目的是通过分析PDAC来源的细胞外囊泡（EVs）的蛋白质组来研究基质硬度对PDAC进展的影响。将PDAC细胞系（mPDAC和KPC）培养在硬度接近非肿瘤（NT）或肿瘤组织（T）的合成支架上，并通过定量无标记质谱分析法分析细胞来源的EVs中的蛋白质表达水平。我们的分析发现，响应基质硬化，mPDAC-EVs中有15种差异表达蛋白（DEPs），KPC-EVs中有20种DEPs。上调的蛋白质参与代谢、基质重塑和免疫反应过程，这些都是PDAC进展的标志。多模态网络分析显示，大多数DEPs与胰腺癌密切相关。有趣的是，根据基因表达谱相互作用分析（GEPIA），在DEPs中，mPDAC-EVs的11个相关基因（ACTB/ANXA7/C3/IGSF8/LAMC1/LGALS3/PCD6IP/SFN/TPM3/VARS/YWHAZ）和KPC-EVs的9个相关基因（ACTB/ALDH2/GAPDH/HNRNPA2B/ITGA2/NEXN/PKM/RPN1/S100A6）在肿瘤组织中显著过表达。关于这些数据的潜在临床相关性，ACTB、ITGA2、GAPDH和PKM基因簇对PDAC患者的总生存期有不良影响（p < 0.05）。
