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

Author

Listed:
  • 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
    Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Richard O. Hynes

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • Chenxi Tian & Ying Huang & Karl R. Clauser & Steffen Rickelt & Allison N. Lau & Steven A. Carr & Matthew G. Vander Heiden & Richard O. Hynes, 2021. "Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22490-9
    DOI: 10.1038/s41467-021-22490-9
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    Cited by:

    1. Michael Papanicolaou & Amelia L. Parker & Michelle Yam & Elysse C. Filipe & Sunny Z. Wu & Jessica L. Chitty & Kaitlin Wyllie & Emmi Tran & Ellie Mok & Audrey Nadalini & Joanna N. Skhinas & Morghan C. , 2022. "Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Sandrine Vadon-Le Goff & Agnès Tessier & Manon Napoli & Cindy Dieryckx & Julien Bauer & Mélissa Dussoyer & Priscillia Lagoutte & Célian Peyronnel & Lucie Essayan & Svenja Kleiser & Nicole Tueni & Emma, 2023. "Identification of PCPE-2 as the endogenous specific inhibitor of human BMP-1/tolloid-like proteinases," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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