Phenotype

Pathology

Cell

Pancreas

Transdifferentiation

Biology

Gene

Cancer

Endocrinology

Paleontology

Ductal cells

Pancreatic Intraepithelial Neoplasia

Context (archaeology)

Metaplasia

Acinar cell

Pancreatic duct

Pancreatic cancer

Mutation

Adenocarcinoma

KRAS

Cancer research

Genetics

Biochemistry

Medicine

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.

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