Updated project metadata. We developed a multidimensional proteomic strategy to profile the glycosylated secreted and plasma membrane (S-PM) proteome of 100 human pancreatic tissue samples to an unprecedented depth, define cell-type origins of these S-PM proteins through spatial proteomics, and identify potential paracrine crosstalk, especially crosstalk mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumor progression were further explored in a genetically engineered PDAC mouse model. Besides, generic shedding of membrane proteins in cancer and stroma regions of PDAC tumors was explored and validated through PRM-based absolute quantification.