Pancreatic ductal adenocarcinoma is characterized by a remarkable phenotypic diversity. The molecular and cellular determinants of this diversity are in large parts not understood. Mutational spectra, for example, could – with very few exceptions – not be associated with different morphologic or clinical phenotypes. Likewise, despite evidence that pancreatic cancer can originate from various terminally differentiated cell types, including acinar, ductal and endocrine cells, it is largely unclear if and how the cell of origin affects pancreatic cancer phenotypes. Understanding the relationship between the genetic changes, the cellular context in which they occur and morphologic/clinical phenotypes has been hampered so far by a lack of tools supporting genome-wide surveys for molecular cancer drivers in different pancreatic compartments.

We have developed transposon-based systems for insertional mutagenesis in mice and propose here to use these tools for genome-wide genetic screening in acinar, ductal and endocrine cells, as well as in pancreatic progenitor cells. This will allow us for the first time to (i) systematically uncover genetic/epigenetic triggers and molecular networks required for de-differentiation and neoplastic transformation of each cell type; and (ii) to examine if and how the cell of origin and the mutational landscape (and their interaction) affect resulting molecular, histopathologic and clinical phenotypes, including tumour initiation/progression, metastatic behaviour, survival and drug response/resistance. We will validate new candidate genes emerging from these screens using novel cellular and in vivo platforms for high-throughput functional genomics, including CIRSPR/Cas9-based approaches for somatic genome engineering in mice, which we have developed recently.

These studies will give comprehensive novel insights into the molecular and phenotypic complexity and plasticity of pancreatic cancer.