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Title: The stellate cancer-associated fibroblast in pancreatic ductal adenocarcinoma : its role in chemoresistance
Author: Johnson, Natalie Georgette
ISNI:       0000 0005 0731 8107
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Introduction: The tumour microenvironment has been found to contribute to cancer survival and progression, and more specifically, the stromal microenvironment has been implicated in the drug resistant nature of cancers such as pancreatic cancer. This microenvironment consists of fibroblasts, pericytes, endothelial cells and the extracellular matrix, with the stellate cancer-associated fibroblast (CAF) being the most predominant cell type present. The aim of this study was to investigate the role of the cancer associated fibroblast in tumourigenesis in Pancreatic Ductal Adenocarcinoma (PDA) with specific reference to the mechanisms involved in chemoresistance via the stellate cancer associated fibroblast. Methods: I investigated the molecular pathogenesis of PDA assessing DNA copy number alterations (CNA) in selection of clinically relevant PDA cell lines (PANC-1, MiaPaCa-2, ASPC-1, SU86.86, HPAC, HS776T, PL5 and PL45), seven primary resected, non immortalised samples (PF3, PF7, PF8, PF9, PF16, PF18 and PF20) and an immortalised stellate cell line using array comparative genomic hybridization (aCGH). All cultures and cell lines were then screened in order to determine their sensitivity to currently used therapeutic compounds. Analysis was done using R software and Graph Pad Prism 5. Results: The non-immortalised stellate CAFs and formalin fixed paraffin embedded stromal fibroblast samples showed no homozygous genomic CNAs. The stellate cancer associated fibroblasts both primary and immortalised appear more responsive to the chemotherapeutic drugs in the compound library compared to the PDA cell lines. Conclusions: This study suggests the absence of homozygous deletions that may lead to a change in phenotype in the stellate CAF. However, the presence of heterozygous deletions and epigenetic changes has not yet been excluded. Further experiments such as micro RNA and epigenetic studies, such as SNP arrays, may identify the presence of aberrations that have aetiological significance in carcinogenesis even if they do not result in CNVs. This higher sensitivity of the stellate CAF to the drugs in the chemotherapy library may favour them as potential targets for management of this hard to street subtype of disease.
Supervisor: Stamp, Gordon; Thillainayagam, Andrew; Spalding, Duncan Sponsor: Institute of Cancer Research ; The London Clinic
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral