Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells

Tian, C., Clauser, K. R., Ohlund, D., Rickelt, S., Huang, Y., Gupta, M., Mani, D. R., Carr, S. A., Tuveson, D. A., Hynes, R. O. (September 2019) Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc Natl Acad Sci U S A, 116 (39). pp. 19609-19618. ISSN 0027-8424

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively 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 and 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 both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated 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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal Investigative techniques and equipment > biomarker bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > extracellular matrix proteins organism description > animal > mammal organism description > animal > mammal > rodent > mouse diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A.
Communities:	CSHL labs > Tuveson lab CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User:	Matthew Dunn
Date:	4 September 2019
Date Deposited:	16 Sep 2019 16:05
Last Modified:	05 Feb 2024 20:41
PMCID:	PMC6765243
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38404

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