Ductal epithelial cells and/or centroacinar cells are believed to harbor progenitor cells and give rise to the common pancreatic adenocarcinoma. While there are experimental models to suggest that there is significant capacity for regeneration within the adult pancreatic tissue, considerable debate exists over whether these events represent true examples of """"""""transdifferentiation"""""""" as opposed to selective expansion of undifferentiated progenitors in ductal cells or centroacinar cells. Furthermore, the molecular basis for pancreatic ductal branching morphogenesis during exocrine development and epithelial carcinogenesis has yet to be elucidated, which might provide new clues as to the events that trigger ductal differentiation, potential transdifferentiation into other cell types, and malignant transformation. The PDX-1 homeodomain transcription factor is of critical importance in endocrine cell lineage specification;however, the molecular regulation of exocrine (specifically ductal cell lineage) remains elusive. We describe in vitro and in vivo evidence that PDX-1 plays a crucial role in the regulation of ductal morphogenesis, using cytokeratin 19 as a surrogate of ductal gene expression. The overarching hypothesis of this proposal is that PDX-1 modulates pancreatic ductal branching morphogenesis, and this goes awry during malignant transformation. Using innovative three-dimensional cell culture systems (spheroid cysts) and Pdx-1 C-terminal mutant knock-in mice, this hypothesis will be pursued by the following interrelated Specific Aims: (1) To determine the molecular mechanisms underlying pancreatic ductal formation, differentiation and migration, termed branching morphogenesis or tubulogenesis, in a three-dimensional cell culture system;(2) To determine the in vivo role of PDX-1 in pancreatic ductal branching morphogenesis;and (3) To characterize terminal intercalated duct-acinar junctional cells and to characterize known factors regulating centroacinar cell proliferation, differentiation and gene expression. The insights gained from these complementary approaches will provide new insights into how pancreatic ducts develop, how they migrate and compartmentalize, and how they undergo malignant transformation. These studies will provide a platform for new molecular diagnostics and targeted therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Boursi, Ben; Finkelman, Brian; Giantonio, Bruce J et al. (2017) A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With New-Onset Diabetes. Gastroenterology 152:840-850.e3
von Burstin, Johannes; Bachhuber, Friedrich; Paul, Mariel et al. (2017) The TALE homeodomain transcription factor MEIS1 activates the pro-metastatic melanoma cell adhesion molecule Mcam to promote migration of pancreatic cancer cells. Mol Carcinog 56:936-944
Zhou, Jin; Wu, Zhong; Wong, Gabrielle et al. (2017) CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun 8:13897
Diersch, S; Wirth, M; Schneeweis, C et al. (2016) Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. Oncogene 35:3880-6
Westphalen, C Benedikt; Takemoto, Yoshihiro; Tanaka, Takayuki et al. (2016) Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. Cell Stem Cell 18:441-55
Takano, Shigetsugu; Reichert, Maximilian; Bakir, Basil et al. (2016) Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev 30:233-47
Yang, Yu-Xiao; Rustgi, Anil K (2016) Impact of Metformin on Advanced Pancreatic Cancer Survival: Too Little, Too Late? Clin Cancer Res 22:1031-3
Rustgi, Anil K (2016) Pancreatic fibroblasts smoothen their activities via AKT-GLI2-TGF?. Genes Dev 30:1911-2
Heeg, Steffen; Das, Koushik K; Reichert, Maximilian et al. (2016) ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. Gastroenterology 151:540-553.e14
Roberts, Nicholas J; Norris, Alexis L; Petersen, Gloria M et al. (2016) Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 6:166-75

Showing the most recent 10 out of 35 publications