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PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance
- Source :
- Genes & development, vol 30, iss 24
- Publication Year :
- 2016
- Publisher :
- Cold Spring Harbor Laboratory Press, 2016.
-
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.
- Subjects :
- 0301 basic medicine
endocrine system diseases
pancreatic cancer
Pancreatic Intraepithelial Neoplasia
pancreatitis
Acinar Cells
medicine.disease_cause
Cell Transformation
Medical and Health Sciences
Mice
Tumor Cells, Cultured
2.1 Biological and endogenous factors
Aetiology
skin and connective tissue diseases
Cancer
Cultured
EMT
Biological Sciences
Chromatin
Tumor Cells
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Cell Transformation, Neoplastic
Pancreatic Ductal
PDX1
Pancreas
Research Paper
Carcinoma, Pancreatic Ductal
medicine.medical_specialty
endocrine system
education
Biology
digestive system
03 medical and health sciences
Rare Diseases
Internal medicine
Pancreatic cancer
Genetics
Acinar cell
medicine
Animals
Humans
Neoplastic transformation
Homeodomain Proteins
Neoplastic
Carcinoma
dedifferentiation
Psychology and Cognitive Sciences
medicine.disease
Pancreatic Neoplasms
030104 developmental biology
Endocrinology
Gene Expression Regulation
Tissue Array Analysis
Cancer research
Trans-Activators
Carcinogenesis
Digestive Diseases
Gene Deletion
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 08909369
- Database :
- OpenAIRE
- Journal :
- Genes & development, vol 30, iss 24
- Accession number :
- edsair.doi.dedup.....2bc1f44bda16660e36877f1810e42dc0