Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation

Jonathan J. Swietlik, Stefanie Bärthel, Chiara Falcomatà, Diana Fink, Ankit Sinha, Jingyuan Cheng, Stefan Ebner, Peter Landgraf, Daniela C. Dieterich, Henrik Daub, Dieter Saur () and Felix Meissner ()
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Jonathan J. Swietlik: Max Planck Institute of Biochemistry
Stefanie Bärthel: German Cancer Research Center and German Cancer Consortium
Chiara Falcomatà: German Cancer Research Center and German Cancer Consortium
Diana Fink: University of Bonn
Ankit Sinha: Max Planck Institute of Biochemistry
Jingyuan Cheng: Max Planck Institute of Biochemistry
Stefan Ebner: University of Bonn
Peter Landgraf: Otto-von-Guericke-University Magdeburg
Daniela C. Dieterich: Otto-von-Guericke-University Magdeburg
Henrik Daub: NEOsphere Biotechnologies GmbH
Dieter Saur: German Cancer Research Center and German Cancer Consortium
Felix Meissner: Max Planck Institute of Biochemistry

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38171-8

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