Abstract
Pancreatic acinar-to-ductal metaplasia (ADM) is a reversible process that occurs after pancreatic injury, but becomes permanent and leads to pancreatic lesions in the presence of an oncogenic mutation in KRAS,. While inflammatory macrophage-secreted chemokines, growth factors that activate epidermal growth factor receptor (EGFR) and oncogenic KRAS have been implicated in the induction of ADM, it is currently unclear whether a common underlying signaling mechanism exists that drives this process. In this study, we show that different inducers of ADM increase levels of hydrogen peroxide, most likely generated at the mitochondria, and upregulate the expression of Protein Kinase D1 (PKD1), a kinase that can be activated by hydrogen peroxide. PKD1 expression in acinar cells affects their survival and mediates ADM, which is in part due to the PKD1 target NF-κB. Overall, our data implicate ROS-PKD1 signaling as a common feature of different inducers of pancreatic ADM.
Highlights
In response to inflammation, growth factor signaling or oncogenic signaling, pancreatic acinar cells can undergo a dedifferentiation process named acinar-to-ductal metaplasia (ADM) [1]
The activation of epidermal growth factor receptor (EGFR) signaling through its ligands, EGF and TGFα, in the acinar cells induces their metaplasia to a duct-like phenotype [23], but the underlying cellular signaling is not well understood
ADM is a reversible process and is involved in pancreatic regeneration when pancreatitis resolves [1]. It was shown in different mouse models that in the presence of an oncogenic KRAS mutation, ADM is irreversible and leads to the development of pancreatic intraepithelial neoplasia (PanIN), which can further develop into pancreatic ductal adenocarcinoma (PDAC) [4,5,12,27]
Summary
Growth factor signaling or oncogenic signaling, pancreatic acinar cells can undergo a dedifferentiation process named acinar-to-ductal metaplasia (ADM) [1]. ADM is characterized by the transcriptional downregulation of acinar cell markers such as amylase and carboxypeptidase A [2], and increased expression of ductal markers, such as cytokeratin 19 (CK19) and mucin-1 [3]. Cells that undergo ADM are in a less-differentiated, duct-like state [1,4,5], and feature the capacity for pancreatic regeneration. ADM cells can be locked into their dedifferentiated state when expressing mutant (active) KRAS. This is an irreversible process, leading to development of low-grade pancreatic lesions, as long as KRAS is active [1,6]. Understanding the signaling processes that drive ADM could provide insight into how the pancreas regenerates after a damaging insult, as well as an understanding of the earliest events driving tumor formation
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