Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22490-9
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Funding
- NIH Pathway to Independence Award [K99CA234221]
- Lustgarten Foundation
- Ludwig Center at MIT
- MIT Center for Precision Cancer Medicine
- SU2C
- NCI [R35CA242379]
- HHMI
- STARR Cancer Consortium
- Howard Hughes Medical Institute
- NCI Cancer Center Support Grants [P30CA14051-45]
- MIT Ludwig Center for Molecular Oncology
- National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium grants [NIH/NCI U24-CA210986, NIH/NCI U01 CA214125]
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The ECM of pancreatic ductal adenocarcinoma has partially uncleaved C-terminal prodomains of fibrillar collagens, indicating reduced procollagen C-proteinase activity. The enzyme BMP1 selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Cancer-cell-derived fibrillar collagen plays a role in selectively restraining tumor growth.
Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.
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