PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Abstract

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice

“…In contrast to the indispensable role of Pdx1 in the formation of acinar cells during embryonic stages , Pdx1 depletion in half of the adult acinar cell mass did not cause any apparently abnormal macroscopic phenotypes; the pancreatic size looked normal, which is consistent with a previous report , and the mutant mice did not become lean or show fatty stools or diarrhea. Though Pdx1‐depleted cells expressed decreased amounts of digestive enzymes such as amylase (Fig.…”

“…model [7], suggesting the involvement of Pdx1 in adult exocrine pancreas homeostasis. Furthermore, Roy et al [8] reported that the combination of Pdx1 inactivation and cerulein-induced pancreatitis causes apoptosis and a reduction in pancreatic mass. However, they also found that Pdx1 depletion in adult acinar cells does not cause a reduction in the amount of exocrine tissue in the absence of pancreatitis.…”

HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells

“…Lastly we sought to gain insight into the transcriptional activity of HNF1A in PDA and determine whether its transcriptome held prognostic information similar to other signatures in PDA (Bailey et al, 2016, Collisson et al, 2011. In order to identify transcriptional targets of HNF1A, we performed Bru-seq, a variation of RNA-seq which measures changes in nascent RNA levels (bone fide transcription rate) as opposed to steady-state RNA changes measured by conventional RNA-seq and microarray (Paulsen et al, 2013).…”

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

“…3A). Since NR5A2 and PDX1 function in pancreatic acinar differentiation and are reportedly linked to PDA initiation and growth 19,40 , we asked whether RNF125 is involved in their regulation also in PDA. RNF125 expression was associated with the expression of both PDX1 and NR5A2 in normal pancreas (Fig.…”