Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Sep 4. pii: 201908626. doi: 10.1073/pnas.1908626116. [Epub ahead of print]

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

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
4
Department of Radiation Sciences, Umeå University, 901 87 Umeå, Sweden.
5
Wallenberg Centre for Molecular Medicine, Umeå University, 901 85 Umeå, Sweden.
6
New York University Winthrop Hospital, Mineola, NY 11501.
7
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; rohynes@mit.edu.
8
Howard Hughes Medical Institute, Chevy Chase, MD 20815.

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.

KEYWORDS:

ECM; PDAC; PanIN; pancreatitis

PMID:
31484774
DOI:
10.1073/pnas.1908626116

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center