Determining the efficacy and safety of cancer chemotherapeutics for cholangiocarcinoma (CCA) using Human Precision Cut Tissue Slices (hPCTS).

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Cholangiocarcinoma (CCA) is a bile duct cancer and one of the worst outcome human malignancies. Late-stage diagnosis and limited therapeutic options means that survival rates are low and it is a cancer of unmet need.Mouse models of hepatobiliary cancer have been generated to unravel the molecular mechanisms that drive this disease. Genetic mutations can be induced chemically or virally to promote tumour formation, alternatively key pathways that drive malignant transformation can be disrupted or 'knocked out' , alongside xenograft models whereby tumour cells are implanted into immunodeficient mice. However, in vivo approaches are costly, time-consuming and raise ethical concerns. Therefore, in vitro alternatives to investigate bile duct cancer progression are urgently needed.Precision cut tumour slices are three-dimensional structures of hepatobiliary cells that can be cultured ex vivo. They recapitulate critical aspects of the hepatobiliary cancer biology and, crucially retain the original tumour microenvironment. In this proposal, we propose to implement the use of precision cut tissue slices derived from human tumour tissue (hPCTS) in our lab to study the molecular mechanisms driving disease progression. Our scientific goal is to establish and validate tumour slice viability in the lab and maintenance of liver and bile duct functionality over time and to ensure that the tumour mutations are retained in culture. We will then assess the ability of hPCTS CCA to respond to Gemcitabine and Cisplatin, anti-cancer drugs that are standard care for bile duct cancer. We will identify invading immune cells and the tumour slice's ability to respond to cancer immunotherapies. Finally, we will confirm their clinical relevance by exposing hPCTS to a panel of molecular targeted anti-cancer drugs to determine their ability to stop tumour growth.Overall, we anticipate that our approach will offer a biologically relevant in vitro model to understand bile duct cancer mutations which can be targeted with anti-cancer drugs, thereby replacing the use of mice to study vital biological aspects of this disease.