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Nat Commun DOI:10.1038/s41467-021-22490-9

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

Publication TypeJournal Article
Year of Publication2021
AuthorsTian, C, Huang, Y, Clauser, KR, Rickelt, S, Lau, AN, Carr, SA, Heiden, MGVander, Hynes, RO
JournalNat Commun
Volume12
Issue1
Pages2328
Date Published2021 04 20
ISSN2041-1723
KeywordsAnimals, Bone Morphogenetic Protein 1, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Collagen Type I, Disease Progression, Extracellular Matrix, Extracellular Matrix Proteins, Fibrillar Collagens, Humans, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mutagenesis, Pancreatic Neoplasms, Procollagen, Protein Domains, RNA, Messenger
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.

DOI10.1038/s41467-021-22490-9
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33879793?dopt=Abstract

Alternate JournalNat Commun
PubMed ID33879793
PubMed Central IDPMC8058088
Grant List030521 / HHMI / Howard Hughes Medical Institute / United States
K99 CA234221 / CA / NCI NIH HHS / United States
R35 CA242379 / CA / NCI NIH HHS / United States
U24 CA210986 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States