Abstracts Category : Other

Investigation into mechanisms of metastasis in breast cancer and pancreatic cancer

by Gemma Moore

The aim of this project was to investigate mechanisms of metastasis in triple negative breast cancer (TNBC) and pancreatic cancer. Metastasis is the ability of a cell to spread to another location colonising a secondary site, which contributes to approximately 90% of cancers fatalities. Both TNBC and pancreatic cancer possess poor prognosis, limited therapeutic options and the risk of each becoming metastatic remains a major risk. This body of work aimed to investigate unique influences on the metastatic capabilities of both TNBC and pancreatic cancer cells. Three critical metastatic phenotypes were investigated, specifically anoikis resistance (anchorage independence), colony formation, proliferation and invasion. Metastasis was investigated through three approaches: i) microarray profiling was used to investigate genes that were differentially expressed in anoikis resistant conditions, ii) an indirect co-culture model that mimicked the tumour microenvironment was used to assess critical metastatic phenotypes in pancreatic cancer and iii) miRNA expression profiling and a range of methods for altering miRNA expression in cell culture were deployed to assess the effect of altered miRNA expression on the metastatic phenotypes of pancreatic cancer.Through microarray profiling 26 genes were identified as differentially expressed in anoikis resistant conditions. Specifically, GRP78 was identified as a regulator of growth in TNBC through proliferation and colony formation, with GRP78 acting as an oncogene. The development of an indirect co-culture model allowed insight into the complicated role of the tumour microenvironment in pancreatic cancer. This investigation led to the observation that the stroma can act to inhibit and restrain the progression of pancreatic cancer. Altering miRNA expression led to the identification of a range of tumour suppressor miRNA including miR-7a, miR-204 and miR-378. Each induced different changes in metastatic phenotypes including a reduction proliferation, colony formation and an extreme increase in invasion. A highly novel finding is the validity of using sponge knockdown vectors as a valuable research tool in pancreatic cancer. In conclusion, anoikis, proliferation, colony formation and invasion were greatly influenced by gene expression, the tumour microenvironment and miRNA expression. Using these three approaches a greater understanding of metastasis and consequently of how both TNBC and pancreatic cancer progress has been gained. With this greater understanding comes a greater possibility of developing effective therapies.Advisors/Committee Members: Breen, Laura, O'Neill, Fiona.