Dokument: Investigations to improve CTC-based liquid biopsy in pancreatic ductal adenocarcinoma by screening high volume of blood
| Titel: | Investigations to improve CTC-based liquid biopsy in pancreatic ductal adenocarcinoma by screening high volume of blood | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=64329 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20231213-111132-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Guglielmi, Rosa [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. rer. nat. Neubauer, Hans [Gutachter] Prof. Dr. Kassack, Matthias [Gutachter] | |||||||
| Stichwörter: | Circulating tumor cells; pancreatic ductal adenocarcinoma; leukapheresis | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Surgical resection combined with systemic therapies remains the only approach with curative intent, but the rapid progression of the disease reduces the chance to detect patients in early stages, when the surgery would be more efficient. The potential of pancreatic circulating tumor cells (CTCs) as liquid biopsy could help to guide therapy.
The main aim of this thesis was to investigate whether screening of large blood volumes could improve CTC detection and characterization. In a first step, the value of diagnostic leukapheresis (DLA) in PDAC was tested. Compared to a conventional blood sample, DLA could significantly increase CTC detection. Interestingly, detection of CTCs was correlated with impaired overall survival. Moreover, PDAC CTCs could be isolated from positive samples and subjected to single cell genomic profiling. This revealed pathogenic mutations in hotspot regions of KRAS and TP53 as well as copy number alterations (CNAs) typical for PDAC, confirming the malignant origin of the isolated marker-positive cells. Besides commonalties, the genomic data also revealed differences with the matched tumor tissue, supporting the notion that CTC-based liquid biopsies can provide additional information on the systemic disease. However, due to their high white blood cells (WBCs) background, current CTC-detection is technically restricted to a fraction (~5%) of whole DLA products, limiting the utility of the approach for clinical applications. Thus, another goal of this work was to test the performance of a label-free spiral microfluidic chip that potentially allows processing of whole DLA products. The data revealed the feasibility of the approach although a loss of 50% of enriched cells was noticeable. DLA biochip efficiently processed up to 400x106 WBCs per run (equivalent to ̴ 120 mL PB) and never clogged. Moreover, a two-cycles enrichment of samples originally containing 400x106 WBCs resulted in the 99.98% of WBC depletion ( ̴ 60,000 WBCs remaining in the enriched sample). In conclusion, it was demonstrated that the screening of high volume of blood allows to detect and analyze pancreatic CTCs, contributing to move towards the use of CTC-based liquid biopsy in PDAC management. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | 2021-2023 | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 13.12.2023 | |||||||
| Dateien geändert am: | 13.12.2023 | |||||||
| Promotionsantrag am: | 17.04.2023 | |||||||
| Datum der Promotion: | 14.11.2023 |
