American Association for Cancer Research
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Figure S3 from Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma

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posted on 2023-03-31, 03:26 authored by Chenxi Tian, Daniel Öhlund, Steffen Rickelt, Tommy Lidström, Ying Huang, Liangliang Hao, Renee T. Zhao, Oskar Franklin, Sangeeta N. Bhatia, David A. Tuveson, Richard O. Hynes

Xenograft tumors knocked down and overexpressing AGRN, SERPINB5, and CSTB show expected protein expression changes.

Funding

STARR Cancer Consortium

Howard Hughes Medical Institute

Lustgarten Foundation

NCI

Koch Institute

Cold Spring Harbor

NIH

DOD

V Foundation

MIT

Swedish Research Council

Kempe Foundations

Swedish Society of Medicine

Västerbotten

Cancer Research Foundation in Northern Sweden

Swedish Foundation for International Cooperation in Research and Higher Education

Knut and Alice Wallenberg Foundation

Swedish Cancer Society

National Institute of Environmental Health Sciences

Ludwig Fund for Cancer Research

the Koch Institute's Marble Center for Cancer Nanomedicine

History

ARTICLE 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. This study provides insights into the biological roles of cancer cell–derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

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