Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2020
- Source ID
- 10.1158/0008-5472.can-19-2578
Entities
People
- Chenxi Tian
- Daniel Öhlund
- David A. Tuveson
- Liangliang Hao
- Oskar Franklin
- Renee T Zhao
- Richard O. Hynes
- Sangeeta N. Bhatia
- Steffen Rickelt
- Tommy Lidström
- Ying Huang
Organizations
- Cancer Research Foundation in Northern Sweden
- Howard Hughes Medical Institute
- Kempe Foundation
- Knut and Alice Wallenberg Foundation
- Lustgarten Foundation for Pancreatic Cancer Research
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institute of Environmental Health Sciences
- National Institutes of Health
- Swedish Research Council
- Swedish Society of Medicine
- Umeå University
- United States Department of Defense
- V Foundation for Cancer Research