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Brian Lewis, PhD is a 2009 recipient of the Pancreatic Cancer Action Network-AACR Pilot Grant. The grant supports his innovative research of "Involvement of miRNAs in Kras-Induced Pancreatic Tumorigenesis."
Dr. Lewis' focus is on the molecular genetics of pancreatic and liver cancers. His lab has generated novel animal models for pancreatic cancer and explores the roles of signaling pathways in disease pathogenesis. Through the analysis of primary tumor specimens, many of the genetic alterations that occur within particular tumor types have been identified. The recent success of targeted cancer therapies, particularly the success of Imatinib (Gleevec), demonstrates that an understanding of the underlying molecular defect(s) can lead to the design of rational, effective therapies. Therefore, one of the overriding goals of his lab is to identify correlations between specific genetic changes, tumor behavior, and signal transduction pathways. With regard to pancreatic cancer, ongoing studies in the lab are aimed at identifying the nature of the transformed cell, identifying the underlying molecular changes that occur in these tumors, and utilizing transgenic animals that express TVA in the ductal or endocrine compartments of the pancreas to identify the effects of oncogene expression in the cell lineages.
Recent work includes:
Morton JP, Klimstra DS, Mongeau ME, Lewis BC. “Trp53 deletion stimulates the formation of metastatic pancreatic tumors.” Am. J. Pathol., in press.
Chen Y-W, Paliwal S, Draheim K, Grossman SR, Lewis BC. (2008) “p19Arf inhibits the invastion of hepatocellular carcinoma cells by binding to CtBP.” Cancer Res. 68: 476-482.
Paliwal S, Kovi RC, Nath B, Chen YW, Lewis BC, Grossman SR. “The alternative reading frame tumor suppressor antagonizes hypoxia-induced cancer cell migration via interaction with the COOH-terminal binding protein corepressor.” Cancer Research. 67(19):9322-9, 2007 Oct 1.
Chen YW, Klimstra DS, Mongeau ME, Tatem JL, Boyartchuk V, Lewis BC. “Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells.” Cancer Research. 67(16):7589-96, 2007 Aug 15.
Morton JP, Lewis BC. “Shh signaling and pancreatic cancer: implications for therapy?” Cell Cycle. 6(13):1553-7, 2007 Jul 1.
Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC. “Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis.” Proceedings of the National Academy of Sciences of the United States of America. 104(12):5103-8, 2007 Mar 20.
Lewis BC. “Development of the pancreas and pancreatic cancer.” Endocrinology & Metabolism Clinics of North America. 35(2):397-404, xi, 2006 Jun.
Lewis BC, Klimstra DS, Socci ND, Xu S, Koutcher JA, Varmus HE. “The absence of p53 promotes metastasis in a novel somatic mouse model for hepatocellular carcinoma.” Molecular & Cellular Biology. 25(4):1228-37, 2005 Feb.
Lewis BC, Klimstra DS, Varmus HE. “The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer.” Genes & Development. 17(24):3127-38, 2003 Dec 15.
JeanMarie Houghton, MD, PhD
JeanMarie Houghton is broadly interested in the contribution of stem cells to cancer. In 2004, Houghton and colleagues published stunning findings in Science that provided a radically different view of the origins of gastric cancers, identifying an unexpected link between stomach cancer and bone marrow-derived stem cells. The investigators discovered that infection with Helicobacter felis (a bacterium related to Helicobacter plyori, which has long been understood to cause chronic inflammation and cancer in the lining of the stomach) leads to a vast influx of bone marrow-derived stem cells as the body tries to repair the damage caused by the bacterial infection. Houghton and collaborators showed that this flood of bone marrow-derived stem cells can actually lead to the development of stomach cancer. This research led to her receipt of the 2006 Presidential Early Career Award for Scientists and Engineers (PECASE). The Presidential Award is the highest honor bestowed by the U.S. government on outstanding scientists and engineers beginning their independent careers.
Dr. Houghton aims to further understand the progression of events that leads to the dire consequence of an influx of stem cells. Specifically, the Houghton lab is studying the signaling mechanisms that direct the stem cells’ actions. The ultimate goal of intervention will be to coax the cells to differentiate normally, or for those cells that have already metastasized, to develop more targeted treatments that spare healthy cells the detrimental effect of current chemotherapies.
She is using this knowledge and expertise to create humanized mouse colonies for patients treated at UMass Memorial with resected pancreatic adenocarcinoma. This has the potential to both impact individual patient care (as novel therapeutics can be tested on tumor-bearing mice) as well as generate a powerful research tool for investigating the molecular and proteomic basis of pancreatic cancer.
Recent work includes:
Houghton J, Korah R, Kim K, Small M. A Role for Apoptosis in the Pathogenesis of AIDS Related Esophageal Ulcers. Journal of Infectious Diseases. 1997 May; 175(5): 1216-9.
Houghton J, Korah R, Condon M, Kim K. Apoptosis in H. pylori Associated Gastric and Duodenal Ulcer Disease is Mediated by the Fas Antigen Pathway. Digestive Diseases and Sciences. 1999 Mar; 44(3): 465-478.
Houghton J, Korah R, Kim K. Fas Receptor Up-regulation and Membrane Localization Concurrent with Apoptosis in IEU- A Study Toward Better Understanding Esophageal Injury in AIDS Journal of Infectious Diseases. 1999 Jul; 180(1): 211-15.
Houghton J, Macera-Bloch L, Harrison L, Korah R. TNF- and IL-1 upregulate gastric mucosal Fas Ag expression in Helicobacter pylori infection. Infection and Immunity. 2000 Mar; 68(3) 1189-1195.
Houghton J, Macera-Bloch L, Goldstein M, Von Hagen S, Korah R. In vivo disruption of the Fas pathway abrogates gastric growth alterations secondary to Helicobacter infection. Journal Infectious Diseases. 2000 Sep; 182(3): 856-64.
Houghton J, Ramamoorthy R, Pandya H, Dhirmalani R, Kim K. Human plasma is directly bacteriocidal against Helicobacter pylori in vitro, potentially explaining the decreased detection of H. pylori during acute upper GI bleeding. Gastrointestinal Endoscopy. 2002 Jan; 55(1) 11-16.
Houghton J, Fox JG, Wang TC. Gastric Cancer: Laboratory Bench to Clinic. J Gastroenterol Hepatol. 2002 April; 17(4): 495-502.
Andrew Leiter, MD, PhD
Dr. Leiter is an internationally recognized expert on the differentiation of endocrine cells in the pancreas and gastrointestinal tract. He is also researching ways to develop better animal models of gastrointestinal and pancreatic neuroendocrine tumors for understanding how they arise.
His research relies heavily on transgenic mice as a model to examine developmental biology in the GI tract. The major areas currently under investigation in the Leiter laboratory include: 1. Identification of precursor cells that give rise to endocrine precursor cells in the GI tract. 2. Elucidation of the role of the Wnt, Rb and Notch signaling pathways in regulating cell fate specification in the GI tract. 3. Characterization of the cells from which human carcinoid tumors originate. 4. Analysis of the mechanism that the basic helix loop helix transcription factor, NeuroDi activates gut hormone expression in cells as they terminally differentiate.
Recent work includes:
Ratineau C, Ronco A, Leiter AB. (2000) “Role of the amino-terminal domain of simian virus 40 early region in inducing tumors in secretin-expressing cells in transgenic mice.” Gastroenterology 119, 1305-1311.
Ratineau C, Petry MW, Mutoh H, Leiter AB. (2002) “Cyclin D1 represses the basic helix-loop-helix transcription factor, BETA2/NeuroD.” J Biol Chem 277, 8847-8853.
Schonhoff SE, Giel-Moloney M, Leiter AB. (2004) “Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types.” Dev Biol 270, 443-454.
Schonhoff SE, Baggio L, Ratineau C, Ray SK, Lindner J, Magnuson MA, Drucker DJ, Leiter AB. (2005) “Energy homeostasis and gastrointestinal endocrine differentiation do not require the anorectic hormone, peptide YY.” Mol Cell Biol. 25, 4189-4199.
Itkin-Ansari P, Marcora E, Geron I, Tyrberg B, Demeterco C, Hao E, Padilla C, Ratineau C, Leiter A, Lee JE, Levine F. “NeuroD1 in the endocrine pancreas: localization and activity as an activator and repressor.” (2005) Dev. Dynamics. 233, 946-953.
Wang Y, Giel-Moloney M, Rindi G, Leiter AB. (2007) “Early enteroendocrine progenitor cells develop tumors in response to Wnt signals but do not require the Wnt pathway for differentiation.” Proc Natl Acad Sci U S A. 104, 11328-11333.
Ray SK, Leiter AB. (2007) “The Basic Helix-Loop-Helix Transcription Factor NeuroD1 Facilitates Interaction of Sp1 with the Secretin Gene Enhancer.” Mol Cell Biol. 27, 7839-7847.
Wang Y, Ray SK, Hinds PW, Leiter AB. (2007) “The retinoblastoma protein, RB, is required for gastrointestinal endocrine cells to exit the cell cycle, but not for hormone expression.” Dev Biol 311, 478-486.
Dr. Urano’s extensive research on the molecular mechanisms of Endoplasmic Reticulum Stress (ER Stress) Diseases such as Alzheimer's disease, Parkinson's disease, Prion disease, ALS and Diabetes Mellitus has led to his interest in studying possible links between ER Stress and Pancreatic Cancer.
The Endoplasmic Reticulum (ER) plays an important role in incubating proteins and maturing them to full function. Since cancer cells grow and spread rapidly, they often suffer from insufficient blood supplies, resulting in areas of nutrient deprivation and hypoxia. This perturbs the sensitive environment in the ER of these cells, leading to ER stress. To mitigate ER stress and survive, cancer cells activate stress signaling pathways, collectively known as the unfolded protein response (UPR), which counteracts ER stress. ER stress signaling is regulated by IRE1 and PERK, enzymes localized to the ER. Our preliminary results indicate not only that PERK has a function in activating the cell survival pathway through a novel component of the UPR, apoptosis antagonizing transcription factor (AATF), but that under ER stress conditions IRE1 regulates vascular endothelial growth factor-A (VEGF-A) mRNA expression, which has an important function in blood vessel formation in tumor cells. Based on these findings, we hypothesize that IRE1 and PERK signaling pathways have important functions in the survival of tumor cells, especially tumors derived from secretory cells, such as pancreatic adenocarcinoma. We are trying to target IRE1 and PERK signaling to lay the groundwork for the development of an effective means of treating pancreatic cancer.
Recent Work Includes:
Luo, D., Yu, L., Zhang, H., He, Y., Urano, F. and Min, W. “AIP1 is critical in transducing IRE1-mediated ER stress response.” J. Biol. Chem., in press.
Lipson, K.L., Ghosh, R. and Urano, F. “The role of IRE1a in the degradation on insulin mRNA in pancreatic beta-cells.” PLoS One, in press.
Chambers, K.T., Unverferth, J.A., Weber, S.M., Wek, R.C., Urano, F. and Corbett, J.A. “The role of nitric oxide and the unfolded protein response in cytokine-induced beta-cell death.” Diabetes, 57(1): 124-132, 2008.
Fonseca, S.G., Lipson, K.L., and Urano, F. “Endoplasmic reticulum stress signaling in pancreatic beta-cells.” Antioxid Redox Signal., 9(12): 2335-244, 2007.
Ishigaki, S., Niwa, J.L., Yamada, S.I., Takahashi, M., Ito, T., Sone, J., Doyu, M., Urano, F., and Sobue, G. “Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.” Neurobiology Dis, 25(2): 331-341, 2007.
Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I, Yoshinaga, K., Shiosaka, S., Hammarback, J.A., Urano, F., and Imaizumi, K. “Autophagy is activated for cell survival after endoplasmic reticulum stress.” Mol Cell Biol, 26(24): 9220-9231, 2006.
Lipson, K., Fonseca, S.G., and Urano, F. “Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes” (Review article). Current Mol Medicine, 6(1): 71-77, 2006.
Lipson, K.L., Fonseca, S.G, Ishigaki, S., Nguyen, L.X., Foss, E., Bortell, R., Rossini, A.A., and Urano, F. “Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1.” Cell Metabolism, 4(3): 245-254, 2006.
Fonseca, S.G.., Fukuma, M., Lipson, K., Nguyen, L.X., Allen, J.R., Oka, Y., and Urano F. “WFS1 is a novel component of the unfolded protein response and maintains ER homeostasis in pancreatic b cells.” J Biol Chem, 280(47): 39609-39615, 2005.
Kubota, K., Lee, D.H., Everett, E.T., Martinez-Mier, E.A., Snead, M.L., Nguyen, L., Urano, F., and Bartlett, J.D. “Fluoride induces ER stress in ameloblasts responsible for dental enamel formation.” J Biol Chem, 280(24): 23194-23202, 2005.
Kadowaki, H., Nishitoh, H., Urano, F., Sadamitsu, C., Matsuzawa, A., Takeda, K., Masutani, H., Yodoi, J., Urano, Y., Nagano, T. and Ichijo, H. “Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.” Cell Death Differ, 12(1): 19-24, 2005.
Kanemoto, S., Kondo, S., Ogata, M., Murakami, T., Urano, F., and Imaizumi, K. “XBP1 activates the transcription of its target gene via an ACGT core sequence under ER stress.” Biochem Biophys Res Commun, 331(4): 1146-1153, 2005.
Allen, J.R., Nguyen, L.X., Sargent, K.E.G., Lipson, K.L., Hackett, A., and Urano, F. “High ER stress in beta cells stimulates intracellular degradation of misfolded insulin.” Biochem Biophys Res Commun, 324: 166-170, 2004.