Pancreatic ductal adenocarcinoma is a relatively uncommon cancer with an almost universally fatal outcome. Chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDA), presumably due to the pro-tumorigenic effects of the inflammatory microenvironment. Besides inflammation, the two diseases have many common features, including ductal metaplasia and fibrosis, both of which may significantly enhance PDA formation. We have found that genetic ablation of the cell surface metalloproteinase ADAM17 specifically from the pancreas makes mice highly resistant to both CP and PDA, thus representing a precise molecular link between these diseases. The purpose of the current proposal is to dissect the mechanisms and define the ADAM17 substrates that contribute to pancreatic disease progression.
In Aim 1 we will use genetic ablation and pharmacological inhibition of ADAM17 substrate-dependent pathways to determine which substrates influence both acinar-to-ductal transdifferentiation and inflammatory cell chemotaxis, in vitro.
In Aim 2, we will use genetic ablation and pharmacological inhibition of the epidermal growth factor receptor (EGFR) and its family member ERRBB3 to test if EGFR ligands released by ADAM17 are responsible for its effects on CP and PDA using in vivo mouse models.
In Aim 3, we will use pharmacological inhibition of ADAM17 released cytokines tumor necrosis factor alpha (TNFa) and interleukin 6 receptor (IL6R) to test for their influence on the etiology of pancreatic inflammation and PDA in vivo.
Pancreatic cancer is virtually always fatal within a very short time after diagnosis. Inflammation of the pancreas has been shown to enhance pancreatic tumor formation. Using genetic mouse models of these diseases, we have found that deletion of the gene encoding the cell surface proteinase ADAM17 protects mice from both pancreatitis and pancreatic cancer formation. The purpose of this proposal is to define the mechanisms by which ADAM17 contributes to these diseases and to assess the potential for designing therapies targeting ADAM17 and the pathways it regulates for treating pancreatic cancer and pancreatitis.
|Halbrook, Christopher J; Wen, Hui-Ju; Ruggeri, Jeanine M et al. (2017) Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis. Cell Mol Gastroenterol Hepatol 3:99-118|
|Saloman, Jami L; Albers, Kathryn M; Li, Dongjun et al. (2016) Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci U S A 113:3078-83|
|Qiu, Wanglong; Tang, Sophia M; Lee, Sohyae et al. (2016) Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS. Gastroenterology 150:218-228.e12|
|Chio, Iok In Christine; Jafarnejad, Seyed Mehdi; Ponz-Sarvise, Mariano et al. (2016) NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell 166:963-976|
|Moris, Maria; Dawson, David W; Jiang, Jennifer et al. (2016) Plectin-1 as a Biomarker of Malignant Progression in Intraductal Papillary Mucinous Neoplasms: A Multicenter Study. Pancreas 45:1353-8|
|Liou, Geou-Yarh; Döppler, Heike; DelGiorno, Kathleen E et al. (2016) Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. Cell Rep 14:2325-36|
|Roy, Nilotpal; Takeuchi, Kenneth K; Ruggeri, Jeanine M et al. (2016) PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. Genes Dev 30:2669-2683|
|Crawford, Howard C (2015) Somatostatin receptor subtype 2 as pancreatic tumorigenesis suppressor: identification of a new targetable signaling node. Gastroenterology 148:1279-81|
|Hoffmann, Franziska S; Kuhn, Peer-Hendrik; Laurent, Sarah A et al. (2015) The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. J Immunol 194:542-52|
|Li, Xue; Maretzky, Thorsten; Weskamp, Gisela et al. (2015) iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling. Proc Natl Acad Sci U S A 112:6080-5|
Showing the most recent 10 out of 33 publications