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Roles of ADAM8 and PRMTs in tumor-stroma-interactions in Pancreatic Ductal Adenocartinoma
The search for new potential biomarkers is a major challenge for oncology, and early detection is key to reducing disease and mortality. Pancreatic ductal adenocarcinoma (PDAC) is a cancer entity with a very poor survival rate. However, its diagnosis in early stages and the interaction partners in t...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2023
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| Zusammenfassung: | The search for new potential biomarkers is a major challenge for oncology, and early detection is key to reducing disease and mortality. Pancreatic ductal adenocarcinoma (PDAC) is a cancer entity with a very poor survival rate. However, its diagnosis in early stages and the interaction partners in tumor stroma cross-talk remains still elusive. Therefore, the main aim of this study is to identify potential diagnostic biomarkers to detect PDAC at early stages.
In this context, extracellular vesicles (EVs) are promising candidates for early PDAC diagnosis. They are released by virtually all cell types but play a poorly understood role in cell communication.
A disintegrin and metalloprotease 8 (ADAM8) which was detected on the surface of serum-EVs by FACS analysis is highly expressed in PDAC and correlates negatively with patient survival. While the function of ADAM8 in PDAC cells is already known, its role in tumor-associated cells remains elusive and no information is available on the expression profile of ADAM8 in cells of TME. Thus, the goal of this study was to analyze the ability of ADAM8-positive EVs isolated from the serum of PDAC patients and miRNAs as cargo of serum EVs, also involving PRMT1 and PRMT4, to distinguish precursor lesions or PDAC fro m healthy controls.
Firstly, to describe the stromal cell types expressing ADAM8 in PDAC, immunohistochemical staining was performed on human PDAC tissue and the results were evaluated. ADAM8 was found to be significantly expressed in macrophages (6 %), natural killer cells (40 %), and neutrophils (63 %), which, among other stromal cells, have the highest percentage of stromal cells expressing ADAM8 in PDAC tissue. From these data, it can be concluded that ADAM8 is not only present in PDAC cells but also in tumor-associated stromal macrophages, NK cells, and neutrophils in the TME and that ADAM8-expressing stromal cells may be a promising parameter that can serve for the early diagnosis of PDAC.
A total cohort of 72 PDAC patients and 20 healthy individuals as a comparison was used in this entire study. All experiments were performed with the same cohort of patients to build an information network about PDAC and its potential biomarkers.
Then, a set of miRNAs as cargo of ADAM8-positive serum EVs, which were differentially expressed in PDAC, were investigated. A downregulation was significantly observed for miRNA-720 and an elevated expression profile for miRNA-451 in PDAC compared to healthy controls to distinguish PDAC from healthy controls. Thus, the detection of miR-720 and miR-451 cargo from ADAM8-positive EVs could provide a specific biomarker and thus a positive contribution to the screening of individuals at risk of PDAC.
To investigate the role of PRMT-1 and 4 on TME in PDAC, immunohistochemical staining was performed with the same stromal cells on human PDAC tissue as previously used to build a network of correlation. The expression levels revealed that PRMT1 promotes the tumor-suppressing effect of p14ARF, a tumor suppressor protein, and a correlation between patient survival and PRMT1 was observed suggesting that PRMT1 is a promising diagnostic marker. Research on PRMT4, which has already been carried out in this work, will be published in a project that has already been started. |
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| Umfang: | 108 Seiten |
| DOI: | 10.17192/z2023.0312 |