This award aims to validate in vitro murine pancreatic premalignant (PanIN) tissue organoids to replace the use of live mice in cancer progression studies from premalignancy to invasive cancer.
Research on pancreatic cancer predominantly uses mice, including genetically altered animals where tumours spontaneously develop. Developing these animal models requires extensive breeding programmes to generate the multiple mutations required to replicate disease. These models are classified as moderate under the UK’s Animals (Scientific Procedures) Act 1986 because of the level of suffering associated with manifestation of the disease. Late stage pancreatic cancer can also be modelled in vitro using organoids derived from either murine or human pancreatic cells. However, as patients are typically diagnosed with late-stage disease, it has not been possible to derive organoids from premalignant tissue. Dr Pedro Perez-Mancera has demonstrated organoids derived from murine PanIN tissue undergo malignant transformation when a tumour suppressor, Trp53, is inactivated. This enables pancreatic cancer progression to be modelled in vitro.
With NC3Rs funding, Pedro will build confidence in the PanIN organoid model and demonstrate its utility. He will downregulate tumour suppressor genes recurrently found inactivated in an in vivo mutagenesis screen and validate this data using the PanIN organoids. Pedro will then evaluate the use of PanIN organoids in therapeutic studies by treating with Gemcitabine, a chemotherapy drug commonly used in treating pancreatic cancer, to determine if the organoids predict a response to the drug. All the findings in the PanIN organoids will then be validated using resected human tissue samples.