GSE90775 PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Contributors : Nilotpal Roy ; Kenneth K Takeuchi ; Jeanine M Ruggeri ; Peter Bailey ; David Chang ; Joey Li ; Laura Leonhardt ; Sapna Puri ; Megan T Hoffman ; Shan Gao ; Christopher J Halbrook ; Yan Song ; Mats Ljungman ; Shivani Malik ; Christopher Wright ; David W Dawson ; Andrew V Biankin ; Matthias Hebrok ; Howard C Crawford
Series Type : Other
Organism : Mus musculus

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for 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 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 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.

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