Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma
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nihms-1558045.pdf
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Accepted version
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3.57 MB
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Author(s)
Tian, Chenxi
Öhlund, Daniel
Rickelt, Steffen
Lidström, Tommy
Huang, Ying
Hao, Liangliang
Zhao, Renee T
Franklin, Oskar
Bhatia, Sangeeta N
Tuveson, David A.
Date Issued
February 2020
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Tian, Chenxi et al. "Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma." Cancer Research 80, 7 (February 2020): dx.doi.org/10.1158/0008-5472.can-19-2578 © 2020 American Association for Cancer Research
Version
Author's final manuscript
Abstract
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell–derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell–derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell–derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1158/0008-5472.can-19-2578
