Abstract
SummaryThe 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains a growing problem, despite efforts to improve diagnosis and therapy
Duct cells exhibit the highest levels of Fbw7 gene expression, and Fbw7 deletion in pancreatic progenitors by Pdx1-Cre leads to an expansion of the ductal compartment (Sancho et al, 2014), suggesting that duct cells might participate in PDAC tumorigenesis following Fbw7 loss
As previously observed (Zhang et al, 2016), Fbw7 deletion greatly accelerated PDAC onset and markedly decreased the median survival of KFC mice compared with KRasG12D Pdx1-Cre (KC) mice without changing the tumor type (Figures S1A–S1D)
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains a growing problem, despite efforts to improve diagnosis and therapy. A better understanding of early PDAC events and cellular biology are needed for improved clinical success (Ying et al, 2016). Four types of pre-neoplastic PDAC precursors have been identified: intraductal papillary mucinous neoplasia (IPMN), pancreatic mucinous cystic neoplasm (MCN), intraductal tubular papillary neoplasm (ITPN), and pancreatic intraepithelial neoplasia (PanIN). PanIN lesions can coexist with other types of pre-neoplastic lesions (Brosens et al, 2015; Verbeke, 2010). This raises important issues regarding the independence and role of different lesions in progressing to PDAC. Understanding the different origins and progression of PDAC tumors will illuminate PDAC biology and could identify better markers allowing patient stratification in the clinic
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