Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression

Summary: The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. : Pancreatic intraepithelial neoplasias (PanINs) are established precursor lesions to pancreatic ductal adenocarcinoma (PDAC). Ferreira et al. show that this model represents acinar-derived PDAC and that, in contrast, duct-derived PDAC does not develop via PanINs. PanIN-like lesions occurring alongside duct-derived tumors arise from adjacent non-mutant tissue and do not represent tumor precursors. Keywords: PDAC, pancreatic cancer, mouse models, progression, PanINs, AGR2, cell of origi