Benedetta Ferrara (Créteil / FR; Milan / IT), Sandrine Bourgoin-Voillard (La Tronche / FR; Grenoble / FR), Damien Habert (Créteil / FR), Benoit Vallée (Créteil / FR), Alba Nicolas-Boluda (Paris / FR), Isidora Simanic (Villejuif / FR), Michel Seve (La Tronche / FR; Grenoble / FR), Benoit Vingert (Créteil / FR), Florence Gazeau (Paris / FR), José Cohen (Créteil / FR), José Courty (Créteil / FR), Ilaria Cascone (Créteil / FR)
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 of 3 and 12 kPa and the protein expression levels in cell-derived EVs were analyzed by a quantitative MSE 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 for mPDAC-EVs and 9 genes for KPC-EVs were significantly overexpressed in tumor-derived tissues according to gene expression profiling interaction analysis (GEPIA). In particular, investigating the potential clinical relevance of these data, the cluster of 3 genes displayed an adverse effect (p < 0.05) on the disease-free survival of PDAC patients.