Genomics

Dataset Information

24

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 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. Overall design: This study consists of 3 Bru-seq samples. Mouse pancreatic cancer cells (NB490) expressing inducible PDX1 shRNA were (1) untreated/uninduced, (2) doxycycline treated for 48 h, or (3) grown-out after 3 weeks of doxycycline treatment.

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Mats Ljungman  

PROVIDER: GSE90775 | GEO | 2017-11-20

SECONDARY ACCESSION(S): PRJNA355880

REPOSITORIES: GEO

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Publications


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 int  ...[more]

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