Preneoplastic Pancreatic (PanIN) Organoids as an in vitro Model of Pancreatic Cancer Progression

Despite advances in our understanding of the molecular pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the overall survival has remained unchanged over recent decades (~6%). There is an urgent and unmet need for understanding the molecular mechanisms driving the progression from a non-lethal preneoplastic stage (Pancreatic Intraepithelial Neoplasia, PanIN) to invasive and lethal PDAC, and to use this knowledge to identify novel options for PDAC therapy. Mouse models of pancreatic cancer have enabled a comprehensive investigation of the genetics and biology of this disease. However, in vivo approaches are costly and time-consuming, and crucially raise ethical concerns. To overcome these limitations, organoids derived from PDAC tissue have been established as a biologically relevant system to study advanced stages of pancreatic cancer, reducing the use of animals. However, the use of organoids derived from pancreatic preinvasive (PanIN) lesions to study the molecular basis of PanIN-to-PDAC progression is still largely unexplored. We have proved that PanIN organoids undergo neoplastic transformation after inactivating Trp53, a key tumour suppressor gene inactivated during PanIN-to-PDAC progression, validating this model to study the biology of pancreatic cancer progression, drastically reducing the number of mice required to perform experiments and ultimately replacing their use. Our scientific goal is to validate the use of PanIN organoids to study pancreatic cancer progression. Experimental data obtained in an in vivo transposon-mediated insertional mutagenesis screen will be validated in PanIN organoids by downregulating tumour suppressor gene candidates found recurrently inactivated in our in vivo screen. Then, we will assess the relevance of PanIN organoids to perform therapeutic studies and predict response to gemcitabine. Finally, we will confirm the clinical significance of PanIN organoids by validating our findings in resected human PDAC specimens.

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Sep 2020 - Mar 2023

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