Abstract
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.
Highlights
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
We found that the primary tumor growth and lung and liver metastasis load resembled the in vitro growth results, in which lenti-bone morphogenetic protein1 (BMP1) reduced and shCOL1A1 promoted tumor growth and metastasis, and shCOL1A1 completely rescued the suppression by lenti-BMP1 (Fig. 5f, g)
These results suggested that the function of BMP1 in suppressing tumor growth and metastasis requires collagen I (ColI) produced by the cancer cells
Summary
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. We further show that the enzyme responsible for procollagen Cproteinase activity, bone morphogenetic protein[1] (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. 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. Our study identifies an unexpected role of ECM including cancer-cellderived fibrillar collagens that is independent of stromally derived fibrillar collagen
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