Why did we fund this project?
This award aims to replace the use of mice in some studies of bile duct cancer using an ex vivo method to culture human tissue slices.
Bile duct cancer is typically studied in mice, either by implanting tumour tissue from patients or through the introduction of relevant genetic mutations. The percentage of mice that possess the mutation as a result of these programmes is small, increasing the number of animals needing to be bred to ensure enough animals for studies. The resulting tumour burden can result in pain, weight loss and other clinical signs associated with suffering. Human tissue can be cultured ex vivo and has a number of advantages over traditional in vitro methods as the precision cut tissue slices retain all relevant cell types in a 3D environment.
Dr Laura Randle will establish human precision cut tissue slices method in her laboratory receiving training, expertise and advice from her European and American collaborators on working with human tissue. Laura will confirm the validate the model for clinical relevance by analysing tissue response to chemotherapy drugs currently used in patient treatment.
Despite advances in our understanding of the molecular pathogenesis of cholangiocarcinoma (CCA), 5-year survival rates have remained unchanged in recent decades (~5%). There is an urgent, unmet need for understanding the molecular basis of this disease and to develop novel targeted therapies.
Mouse models of hepatobiliary cancer have enabled a comprehensive investigation of the genetics and biology of this disease. However, in vivo approaches are costly and timeconsuming, and crucially raise ethical concerns. Precision cut tissue slices (PCTS) offer an alternative as they retain all cell types in their natural 3D tissue environment, in the correct proportions and orientations. Recent modifications to media composition and incubation conditions have improved slice viability and maintenance of phenotype over time.
The aim of this proposal is to establish and validate the use of the use of human PCTS from resected CCA tumour tissue, as an in vitro model to study the molecular pathogenesis of CCA, and assess their relevance to perform therapeutic studies. This technique will replace the need to conduct animal experiments to investigate disease progression and provide a translational model, highlighted in the 2020 CCA consensus statement as an urgent requirement.
Our scientific goal is to validate tumour slice viability, maintenance of hepatobiliary functionality and tumour mutational burden ex vivo. We will then assess the relevance of hPCTS CCA to perform therapeutic studies utilising Gemcitabine/Cisplatin (first line therapy) alongside involvement of invading immune cells and the tumour microenvironment to assess their ability to respond to immunotherapies. Finally, we will confirm their clinical relevance by exposing hPCTS to a panel of chemotherapeutics to determine their efficacy and safety alongside targeted therapies directed by CCA mutational analysis recently identified in our applicant group to inform clinical strategy and management.