Surveying the serologic proteome in a tissue-specific kras(G12D) knockin mouse model of pancreatic cancer

We have applied a serologic proteomic workflow involving three complementary MS approaches to a tissue-specific KrasG12D -knockin mouse model of pancreatic cancer that consistently forms pre-cancerous lesions by four months of age. The three proteomics applications were highly complementary and allowed us to survey the entire range of low to high molecular weight serologic proteins. Combined, we identified 121 (49 downward arrow, 72 upward arrow) unique and statistically relevant serologic biomarkers with 88% previously reported to be associated with cancer and 38% specifically correlated with pancreatic cancer. Four markers, lysozyme C2, cytokeratin 19, Serpina1A, and Pcf11, were further verified by Western blotting. When applying systems analysis, the top associated gene ontology functions were tied to wound healing, RXR signaling, growth, differentiation, and innate immune activation through the JAK/STAT pathway. Upon further investigation of the apparent immune response using a multiplex cytokine screen, we found that IFN-gamma, VEGF, and GM-CSF were significantly increased in serum from the KrasG12D animals compared to littermate controls. By combining three complementary MS applications, we were able to survey the native intact peptidome and the global proteome in parallel, unveiling pathways that may be biologically relevant to promotion of pancreatic cancer progression and serologic markers of non-invasive early-stage neoplasia. This article is protected by copyright. All rights reserved.