The pancreas is a complex organ with exocrine and endocrine functions that are a product of different cell lineages. It is generally believed that """"""""precursor"""""""" cells reside in the developing pancreatic epithelium and give rise to ductal, acinar and islet cells. However, it is unclear what features distinguish such """"""""precursor"""""""" cells and what cues trigger these cells to """"""""transdifferentiate"""""""" into the different lineages. In addition, how these cell fate decisions are altered during pathological conditions of the pancreas, e.g. pancreatic ductal adenocarcinoma, also requires elucidation. Two important molecules that serve as """"""""markers"""""""" of the lineages include keratin 19 (K19) for ductal epithelial cells and the PDX-1 transcription factor for beta islet cells based upon our studies and that of other groups. We have demonstrated that the K19 promoter is transcriptionaly active in pancreatic ductal epithelial cells (mediated by the GKLF/KLF4 transcription factor) but not in acinar cells. Furthermore, when the K19 promoter is fused to the lacZ reporter gene in transgenic mice, there is evidence of beta-galactosidase expression in pancreatic ductal but not acinar cells. When mice bearing a non-inducible Cre """"""""knock-out"""""""" into the K19 locus are bred onto the Rosa26r reporter gene background, beta-galactosidase expression is largely confined to ducts. Thus, we hypothesize that K19 is associated with pancreatic ductal epithelial cell development and cell fate decisions, thereby permitting us to conduct lineage tracings in a rigorous fashion during development and adulthood. We can also dissect the conversion of the normal ductal phenotype into a premalignant/malignant phenotype. The following Specific Aims will be pursued: 1) to determine the transcriptional regulation of the K19 promoter by PDX-1 in different cell lineages and assess whether KLF4 and PDX-1 cooperate in this regulation; 2) To determine differentiation capacities of K19 expressing ductal epithelial cells in mouse pancreas during normal pancreatic development and in adult pancreas. This will be achieved by the generation and characterization of mice in which an inducible Cre recombinase is directed by the K19 promoter and bred into the Rosa26r background, allowing for temporally regulated labeling of K19-positive cells and their molecule progeny; and 3) To generate and characterize K19-mutated Ki-rats transgenic mice in order to determine the molecular basis for ductal metaplasia, a precursor to cancer. In addition, complementary approaches will be utilized to model ductal metaplasia in vitro. In summary, our interrelated studies will provide insights into cell fate decisions during pancreatic development and in adult pancreas and furnish a foundation to define the basis for premalignant stages in pancreatic ductal oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060694-02
Application #
6620665
Study Section
Special Emphasis Panel (ZRG1-RAP (03))
Program Officer
Serrano, Jose
Project Start
2002-04-15
Project End
2007-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
2
Fiscal Year
2003
Total Cost
$261,002
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moreira, Leticia; Bakir, Basil; Chatterji, Priya et al. (2018) Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer. Cell Mol Gastroenterol Hepatol 5:289-298
Das, Koushik K; Heeg, Steffen; Pitarresi, Jason R et al. (2018) ETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis. Dev Dyn 247:854-866
Reichert, Maximilian; Bakir, Basil; Moreira, Leticia et al. (2018) Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. Dev Cell 45:696-711.e8
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
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
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
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
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
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

Showing the most recent 10 out of 37 publications