ABSTRACT: Tian C, Clauser KR, Ohlund D, Rickelt S, Huang Y, Lidstrom T, Franklin O, Gupta M, Mani DR, Carr SA, Tuveson DA, and Hynes RO. PNAS 2019. Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments, yet cannot be non-selectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass-spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas, pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early upregulated group of matrisome proteins in PanIN, which are further upregulated in PDAC and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.
Steven A. Carr 