Cell-selective proteomics is emerging as a powerful concept for studying heterocellular processes. However, its potential to dissect intercellular signaling has not been exploited, despite its promise to identify non-cell autonomous disease mechanisms or biomarkers. Here, we devised an improved azidonorleucine-based protein labeling, enrichment, and mass spectrometry workflow, to achieve comprehensive proteome coverage of up to >10,100 cell-selective proteins. We provide proof-of-concept for in depth cell-selective secretomics by dissecting bidirectional intercellular signaling between co-cultured primary pancreatic ductal adenocarcinoma (PDAC) cells and macrophages. In vivo, detection of extracellular proteins emerged as a unique strength compared to FACS-based methods. Our analysis reveals systematic differences of cancer cell-derived matrisome proteins between molecular PDAC subtypes in vivo, such as elevated EMT-signal sustaining proteins. Intriguingly, high levels of pre-metastatic niche formation-associated factors in the serum reflected tumor activity in circulation. Our findings highlight how cell-selective proteomics accelerates the discovery of diagnostic markers and new therapeutic targets in cancer.