Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma

Objective Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown. Design We examined the contribution of cellular origin to PDAC development by inducing PDAC associated mutations, Kras(G12D) expression and Trp53 loss, specifically in ductal cells (Sox9CreER; Kras(LSL-G12D); Trp53(flox/flox) (' Duct: KPcKO')) or acinar cells (Ptf1a(CreER); Kras(LSL-G12D); Trp53(flox/flox) ('Acinar: KPcKO')) in mice. We then performed a thorough analysis of the resulting histopathological changes. Results Both mouse models developed PDAC, but Duct: KPcKO mice developed PDAC earlier than Acinar: KPcKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct: KPcKO mice. In contrast, Acinar: KPcKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanIN s with delayed progression to PDAC. Acinar-cellderived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions. Conclusion T hese findings indicate that ductal cells are primed to form carcinoma in situ that become invasive PDAC in the presence of oncogenic Kras and Trp53 deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.