1. PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance
- Author
-
Yan Song, Jeanine M. Ruggeri, Mats Ljungman, Christopher V.E. Wright, David K. Chang, Laura Leonhardt, Howard C. Crawford, Matthias Hebrok, David W. Dawson, Shan Gao, Shivani Malik, Kenneth K. Takeuchi, Joey H. Li, Megan T. Hoffman, Sapna Puri, Nilotpal Roy, Andrew V. Biankin, Christopher J. Halbrook, and Peter Bailey
- 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 - 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.
- Published
- 2016