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Sueca Comes, Mireia (2023) The role of mesenchymal cells in cholangiocarcinoma. PhD thesis, University of Nottingham.

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Abstract

The process of tumour formation and progression is highly influenced by the components of the tumour microenvironment (TME) through a mutual and dynamic crosstalk. Cholangiocarcinoma (CCA) is a highly desmoplastic tumour; however, the role of its reactive TME is not fully elucidated. Treatments are limited and often ineffective due to the lack of biomarkers for its early diagnosis and the lack of understanding of its molecular pathogenesis. Therefore, we believe that investigating the TME and its role in CCA progression could lead to more effective therapeutic treatments for managing this devastating cancer.

Spheroid models were established from CCA patient-derived xenografts and a range of cell-lines. The models were characterised by live/dead staining; and stained for H&E, Vimentin (mesenchymal marker) and CK7 and CK19 (CCA markers). The effect of the mesenchymal stem cells (MSCs) in driving proliferation was evaluated by luminescence and Ki-67 staining. The transcriptome was also sequenced and analysed to identify potential signalling pathways that may be driving the proliferation.

CCA-derived spheroids remained viable, retained histological features frequently found in CCA tumours and stained positive for the hepatobiliary markers, confirming that it is a relevant system to investigate CCA. Interestingly, cell proliferation was found to be significantly promoted by the presence of mesenchymal cells. In the PDX-based models, it was also noted that the presence of stromal support enhanced the formation of spheroids, highlighting the importance of the crosstalk with the TME. In addition, RNA-sequencing expression data showed that the ECM-receptor and PI3K-AKT signalling pathways were upregulated in the presence of MSCs.

These results indicate that CCA proliferation could be driven by the crosstalk between the tumour and the stroma through these signalling pathways, and ultimately these pathways could be promising targets for the treatment of this disease.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Grabowska, Anna M. Bates, David O.
Keywords:	Cholangiocarcinoma; Tumour microenvironment; Tumour progression; Signalling pathways
Subjects:	W Medicine and related subjects (NLM Classification) > WI Digestive system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	72002
Depositing User:	Sueca Comes, Mireia
Date Deposited:	28 Jul 2023 04:40
Last Modified:	06 Dec 2023 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/72002

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