Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

Chenxi Tian, Ying Huang, Karl R. Clauser, Steffen Rickelt, Allison N. Lau, Steven A. Carr, Matthew G. Vander Heiden and Richard O. Hynes ()
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Chenxi Tian: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Ying Huang: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Karl R. Clauser: Broad Institute of MIT and Harvard
Steffen Rickelt: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Allison N. Lau: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Steven A. Carr: Broad Institute of MIT and Harvard
Matthew G. Vander Heiden: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Richard O. Hynes: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22490-9

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