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3D co-culture spheroid drug screening platform for pancreatic cancer invasion

Student thesis: Doctoral ThesisDoctor of Philosophy

Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of death by cancer in the UK, accounting for 5% of all cancer deaths in the UK. Only 8% of the PDAC patients from all stages combined, survives for 5 years or longer. Late stage diagnosis combined with early cancer cell dissemination and poor response to current available treatments highlights the need for novel therapeutics tackling tumour growth and invasion.
Previously, it has been shown that cellular plasticity during disease progression and the tumour stroma could contribute to cancer metastasis and resistance to therapy. Furthermore, progression in genetic sub-type classification of PDAC has shown differences in patient survival and response to treatment. However, PDAC cell plasticity and morphology in the presence of matrix has not been extensively addressed nor linked with sub-types thus far. Moreover, while 3D models are increasingly applied in order to mimic in vivo conditions more closely, the majority of current screening assays do not include components of the stroma and are based mainly on cell viability. In addition, well established genetic engineered mouse models (GEMM) and patient derived xenograft (PDX) are not cost effective or widely accessible for screening purposes. Understanding the behavioural characteristics and drug responses of PDAC cells with models mimicking the in vivo microenvironment is pivotal in developing novel therapies.
To address the need for invasion models that can be used for screening, I have first investigated PDAC cell behaviour with the 2.5D model in vitro and selected a representative cell line for screening. Subsequently, I have developed and optimised a 3D co-culture spheroid screening platform to assess compounds for inhibition of PDAC invasion in the presence of pancreatic stellate cells. A select drug library with 99 FDA approved compounds was probed for potential drug repurposing for PDAC invasion and selected for further validation. Together these experiments will provide us novel insight into the invasive behaviour of pancreatic cancer cells and identify potential novel molecular targets against PDAC cell invasion.
Original languageEnglish
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Award date2018

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