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Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.ORCID iD: 0000-0002-5847-2778
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
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2020 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 7, p. 1461-1474Article in journal (Refereed) Published
Abstract [en]

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), SER-PINB5 (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. Significance: 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.

Place, publisher, year, edition, pages
The American Association for Cancer Research , 2020. Vol. 80, no 7, p. 1461-1474
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-170407DOI: 10.1158/0008-5472.CAN-19-2578ISI: 000522833600009PubMedID: 32029550Scopus ID: 2-s2.0-85082807348OAI: oai:DiVA.org:umu-170407DiVA, id: diva2:1428747
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2023-03-24Bibliographically approved
In thesis
1. Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5
Open this publication in new window or tab >>Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Immunosuppresiva och metastasfrämjande matrsomproteiner i pankreascancer : effekten av galectin-4 och SERPINB5
Abstract [en]

In Sweden 1200-1300 people are diagnosed with pancreatic ductal adenocarcinoma (PDAC) every year. Late diagnosis, together with poor treatment response and resistance to checkpoint inhibitor immunotherapy, contributes to the poor prognosis of the disease. 

PDAC is characterized by abundant deposits of extracellular matrix, which mainly includes structural proteins including collagens, proteoglycans, cell-binding glycoproteins, carbohydrates, and secreted proteins, all constituting the matrisome of the tumor. The matrisome protects cancer cells and affects the outcome. Several highly expressed matrisome proteins are involved in oncogenesis, including the processes of immunosuppression and metastasis formation, therefore contributing to the poor prognosis. In this thesis the pathophysiological role of several matrisome proteins in PDAC tumor progression was studied. Unbiased analysis of matrisome proteins in PDAC tumors revealed increased levels of cancer cell-derived secreted proteins compared to normal healthy control tissue. Subsequently, differentially expressed candidate proteins, with known cellular functions in other disease but hitherto uncharacterized role in PDAC progression, were selected.

Serine protease inhibitor clade B member 5 (SERPINB5), agrin, and cystatin B (CSTB), were selected for the study described in paper I based on their known roles in the metastasis formation process in other types of cancers. SERPINB5, agrin and CSTB were found to increase metastasis in models of PDAC by affecting epithelial to mesenchymal transition, ECM degradation and extravasation. In PDAC tumors, high levels of extracellular SERPINB5 correlated to reduced overall survival.  

Galectin 4 (Gal 4) was selected for the study described in paper II based on its known immunosuppressive effects. Gal 4 is highly expressed in PDAC and was found to inhibit T cell infiltration and induce apoptosis in CD8+ T cells by binding to CD3 on the surface of T cells. Gal 4 was associated with better survival in PDAC patients and correlated to higher activation and cytolytic effect of CD8+ T cells.

The relation between gal 4 and other immunosuppressive proteins was studied in paper III. Analysis of available datasets revealed that gal 4 expression correlates with other cancer cell-derived immunosuppressive proteins of the galectin family, galectin 3 and galectin 9, while negatively correlating with the stroma-derived factors galectin-1 and TGFBI.

Findings in this thesis show that targeting of matrisome proteins in PDAC can be a promising therapy strategy. Blocking extracellular SERPINB5 could result in reduced metastasis and increased survival. Blocking intracellular gal 4 could increase anti-tumor immunity and synergize with checkpoint inhibition therapy.

The identified co-expression and coregulation of different immunosuppressive proteins indicate that different tumors can be classified based on their predominant immunosuppressive mechanisms. Following this classification in individual patients, combinations of therapies against different immunosuppressive mechanisms could represent a promising strategy to introduce effective immunotherapies for PDAC patients.  

Place, publisher, year, edition, pages
Umeå: Umeå University, 2022. p. 87
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2207
Keywords
pancreatic cancer, galectin 4, immunotherapy, SERPINB5, metastasis, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Oncology; Immunology; Medicine
Identifiers
urn:nbn:se:umu:diva-201043 (URN)978-91-7855-941-1 (ISBN)978-91-7855-942-8 (ISBN)
Public defence
2022-12-09, Hörsal B, 9 trappor, byggnad 1D, Umeå, 13:00 (English)
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Available from: 2022-11-18 Created: 2022-11-16 Last updated: 2022-11-17Bibliographically approved

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Öhlund, DanielLidström, TommyFranklin, Oskar

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