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

Abstract

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:KP^cKO ')) or acinar cells (Ptf1a^CreER;Kras^LSL-G12D;Trp53^flox/flox ('Acinar:KP^cKO ')) in mice. We then performed a thorough analysis of the resulting histopathological changes.

Results: Both mouse models developed PDAC, but Duct:KP^cKO mice developed PDAC earlier than Acinar:KP^cKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct:KP^cKO mice. In contrast, Acinar:KP^cKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanINs with delayed progression to PDAC. Acinar-cell-derived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions.

Conclusion: These 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.

Keywords: lineage tracing; pancreatic cancer; tumor development; tumor heterogeneity.