Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells
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, w...
| Main Authors: | , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Proceedings of the National Academy of Sciences
2020
|
| Online Access: | https://hdl.handle.net/1721.1/126050 |
| _version_ | 1811069675440701440 |
|---|---|
| author | Tian, Chenxi Clauser, Karl R. Öhlund, Daniel Rickelt, Steffen Huang, Ying Gupta, Mala Mani, D. R. Carr, Steven A. Tuveson, David A. Hynes, Richard O |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Tian, Chenxi Clauser, Karl R. Öhlund, Daniel Rickelt, Steffen Huang, Ying Gupta, Mala Mani, D. R. Carr, Steven A. Tuveson, David A. Hynes, Richard O |
| author_sort | Tian, Chenxi |
| collection | MIT |
| description | 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 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 pathwayswere 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. |
| first_indexed | 2024-09-23T08:14:09Z |
| format | Article |
| id | mit-1721.1/126050 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:14:09Z |
| publishDate | 2020 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1260502022-09-23T11:49:32Z Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells Tian, Chenxi Clauser, Karl R. Öhlund, Daniel Rickelt, Steffen Huang, Ying Gupta, Mala Mani, D. R. Carr, Steven A. Tuveson, David A. Hynes, Richard O Koch Institute for Integrative Cancer Research at MIT 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 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 pathwayswere 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. 2020-07-02T13:48:20Z 2020-07-02T13:48:20Z 2019-09 2019-05 2019-12-09T18:26:18Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 https://hdl.handle.net/1721.1/126050 Tian, Chenxi et al. "Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells." Proceedings of the National Academy of Sciences 115, 39 (September 2019): 19609-19618 © 2019 National Academy of Sciences en http://dx.doi.org/10.1073/pnas.1908626116 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Tian, Chenxi Clauser, Karl R. Öhlund, Daniel Rickelt, Steffen Huang, Ying Gupta, Mala Mani, D. R. Carr, Steven A. Tuveson, David A. Hynes, Richard O Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title | Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title_full | Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title_fullStr | Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title_full_unstemmed | Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title_short | Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| title_sort | proteomic analyses of ecm during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells |
| url | https://hdl.handle.net/1721.1/126050 |
| work_keys_str_mv | AT tianchenxi proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT clauserkarlr proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT ohlunddaniel proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT rickeltsteffen proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT huangying proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT guptamala proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT manidr proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT carrstevena proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT tuvesondavida proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells AT hynesrichardo proteomicanalysesofecmduringpancreaticductaladenocarcinomaprogressionrevealdifferentcontributionsbytumorandstromalcells |