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Free keywords:
TRANSFER-RNA SYNTHETASE; DUCTAL ADENOCARCINOMA; MACROPHAGE POLARIZATION;
CLICK CHEMISTRY; LYSYL OXIDASE; IDENTIFICATION; METASTASIS;
QUANTIFICATION; SPECIFICITY; ENRICHMENTScience & Technology - Other Topics;
Abstract:
"In-depth cell-selective proteomics and secretomics has remained challenging. Here, the authors devise an optimised azidonorleucine labelling, mass spectrometry method and detect over 10,000 proteins in a pancreatic ductal adenocarcinoma model.
Cell-selective proteomics is a powerful emerging concept to study heterocellular processes in tissues. However, its high potential to identify non-cell-autonomous disease mechanisms and biomarkers has been hindered by low proteome coverage. Here, we address this limitation and devise a comprehensive azidonorleucine labeling, click chemistry enrichment, and mass spectrometry-based proteomics and secretomics strategy to dissect aberrant signals in pancreatic ductal adenocarcinoma (PDAC). Our in-depth co-culture and in vivo analyses cover more than 10,000 cancer cell-derived proteins and reveal systematic differences between molecular PDAC subtypes. Secreted proteins, such as chemokines and EMT-promoting matrisome proteins, associated with distinct macrophage polarization and tumor stromal composition, differentiate classical and mesenchymal PDAC. Intriguingly, more than 1,600 cancer cell-derived proteins including cytokines and pre-metastatic niche formation-associated factors in mouse serum reflect tumor activity in circulation. Our findings highlight how cell-selective proteomics can accelerate the discovery of diagnostic markers and therapeutic targets in cancer.
