The exocrine pancreas has a remarkable ability to regenerate after injury, as illustrated in acute pancreatitis, and subsets of chronic pancreatitis. Acinar-ductal metaplasia (ADM) is critical in the ability of the exocrine pancreas to regenerate or permit progression to a preneoplastic state (pancreatic intraepithelial neoplasia or PanIN). Expression of oncogenic Kras* (=mutant Kras) in the mouse pancreas leads to formation of PanIN lesions with long latency, indicating the need for genetic and possibly epigenetic ?second hits?. Chronic pancreatitis is recognized as a strong risk factor for pancreatic ductal adenocarcinoma (PDA) in humans. In mouse models of pancreatic cancer, induction of either acute or chronic pancreatitis results in tissue-wide ADM that is followed by rapid repair (we designate this as ?Adaptive? ADM). However, in the presence of oncogenic Kras*, repair is impaired and ADM progresses to PanIN lesions (we designate this as ?Oncogenic? ADM). Currently, the mechanisms underlying the formation of ADM and how ADM progresses to PanIN in the presence of mutant Kras* remain unknown. Recently, our group performed gene expression analysis of murine ductal cells isolated from the developing pancreas, acute pancreatitis (ADM), and PanIN expressing oncogenic KrasG12D, and compared the expression profiles to that of normal pancreatic ductal cells, resulting in nearly 80 potential genes of interest. Prrx1 (paired-related homeobox 1) was the most differentially regulated transcription factor in all three processes, followed by Etv5, a member of the Ets family of transcriptional factors. Based upon compelling published and preliminary data, we hypothesize that Etv5 and Prrx1 are involved in the initiation and maintenance of ADM, respectively, following pancreatitis. Furthermore, we hypothesize that this regulation allows for subsequent transformation by oncogenic Kras*, thereby promoting progression to PanIN. This hypothesis will be tested through the following interrelated Specific Aims: (1) To determine if Prrx1 is required for ADM and PanIN following pancreatic injury; (2) To elucidate the relationship between Etv5 and Sox9 in the functional regulation of ADM; and (3) To identify and evaluate gene targets of Prrx1 and iKras* (inducible mutant Kras) in the development of ?Oncogenic? ADM (to PanIN).
This aim will identify effectors of Prrx1 and iKras*. Our innovative and integrated research will define the transcriptional regulation of ADM and provide a basis for new perspectives in the therapy of pancreatitis and PanIN.

Public Health Relevance

Pancreatitis, both acute and chronic, is a health burden in the United States. We seek to understand the transcriptional regulation of acinar-ductal metaplasia needed for pancreatic tissue repair and regeneration as a basis for new approaches in therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Serrano, Jose
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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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
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
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

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