PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Roy, N. et al. (2016) PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. Genes and Development, 30(24), pp. 2669-2683. (doi: 10.1101/gad.291021.116) (PMID:28087712)

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.

• Item Type: Articles
• Additional Information: This work was supported by National Institutes of Health/National Cancer Institute grants P30CA046592 to the University of Michigan Comprehensive Cancer Center, R01CA172045 and R01CA112537 to M.H., and R01 CA159222 to H.C.C.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bailey, Dr Peter and Biankin, Professor Andrew and Chang, Professor David
• Authors: Roy, N., Takeuchi, K. K., Ruggeri, J. M., Bailey, P., Chang, D., Li, J., Leonhardt, L., Puri, S., Hoffman, M. T., Gao, S., Halbrook, C. J., Song, Y., Ljungman, M., Malik, S., Wright, C. V.E., Dawson, D. W., Biankin, A. V., Hebrok, M., and Crawford, H. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Genes and Development
• Publisher: Cold Spring Harbor Laboratory Press
• ISSN: 0890-9369
• ISSN (Online): 1549-5477
• Copyright Holders: Copyright © 2016 Roy et al.
• First Published: First published in Genes and Development 30(24): 2669-2683
• Publisher Policy: Reproduced in accordance with the publisher copyright policy