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Last Name

Brian Lewis PhD

Endowed TitleGeorge F. Booth Chair in the Basic Sciences
InstitutionUniversity of Massachusetts Medical School
DepartmentMolecular, Cell and Cancer Biology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB-521
Worcester MA 01605
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentMolecular, Cell and Cancer Biology

    InstitutionUMMS - School of Medicine
    DepartmentProgram in Molecular Medicine

    InstitutionUMMS - School of Medicine
    DepartmentRadiation Oncology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentCancer Biology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentTranslational Science

    Collapse Biography 
    Collapse education and training
    University of California, Los Angeles, Los Angeles, CA, United StatesBSBiology
    Johns Hopkins University, Baltimore, MD, United StatesPHDHuman Genetics & Molecular Bio

    Collapse Overview 
    Collapse overview

    Academic Background

    Brian Lewis received his B.S. in Biology from the University of California, Los Angeles in 1991, and his Ph.D. from Johns Hopkins University in 1997. He performed postdoctoral studies at the NIH and Memorial Sloan-Kettering Cancer Center, supported by a Helen Hay Whitney Foundation postdoctoral fellowship. He is currently supported by a Burroughs Wellcome Fund Career Development Award in the Biomedical Sciences. Dr. Lewis joined the Program in Gene Function and Expression at the University of Massachusetts Medical School as an Assistant Professor in the winter of 2003.

    Molecular Genetics of Pancreatic and Liver Cancers

    Brian Lewis, Ph.D.

    Human solid tumors are marked by the presence of multiple genetic and epigenetic alterations. Through the analysis of primary tumor specimens, many of the genetic alterations that occur within particular tumor types have been identified. However, the specific molecular events that occur downstream of these genetic changes, and the mechanisms by which they influence tumor initiation, progression, and metastasis are still poorly understood. The recent success of targeted cancer therapies, particularly the success of Imatinib (Gleevec), demonstrates than an understanding of the underlying molecular defect(s) can lead to the design of rational, effective therapies. Therefore, one of the overriding goals of our lab is to identify correlations between specific genetic changes, tumor behavior, and signal transduction pathways.

    We utilize novel mouse models generated with the RCAS-TVA gene delivery system (Fisher et al., 1999). RCAS retroviral vectors are based on an avian retrovirus, ALV, whose entry into target cells is mediated by its receptor, TVA. TVA is an avian gene and is not present in the genomes of mammals, such as humans and mice. Therefore, specific tissues within mice can be rendered susceptible to infection by RCAS viruses through the tissue-specific (e.g. pancreas-specific) transgene expression of TVA. We have utilized this technology to generate models for pancreatic and hepatic carcinomas.

    Pancreatic Cancer

    The pancreas is composed of three major compartments: the acinar cells that produce digestive enzymes; the ducts that conduct these enzymes to the gut; and the endocrine cells that produce hormones involved in glucose homeostasis. In humans, tumors derived from each of these compartments have been identified. Furthermore, the genetic alterations identified in each of these tumor types differ. To study these tumor types we have generated transgenic animals that express TVA in each of these compartments.

    Using mice expressing TVA in acinar cells we have demonstrated that the histologic type of the tumor induced is dependent on the inciting oncogene. Polyoma midde T antigen (PyMT) induces acinar and ductal tumors. In contrast, c-myc induces pancreatic endocrine tumors. Furthermore, the tumors express the protein Pdx1, a transcription factor that identifies early pancreatic progenitor cells. Our findings suggest that, at least in this model, the pancreatic tumor type is dependent on the intiating genetic lesions, and that a pancreatic progenitor cell may be the target for oncogenic transformation.

    Ongoing studies in the lab are aimed at:

    1. identifying the nature of the transformed cell;
    2. identifying the underlying molecular changes that occur in these tumors;
    3. utilizing transgenic animals that express TVA in the ductal or endocrine compartments of the pancrease to identify the effects of oncogene expression in the cell lineages.

    Hepatocellular Carcinoma

    Hepatocellular carcinoma afflicts over 250,000 people annually worldwide. Most cases are associated with chronic hepatitis virus infection or causes of chronic liver damage. Common genetic events associated with the disease include loss of the p53 tumor suppressor gene.

    We have generated transgenic animals that express TVA specifically within the liver. Delivery of RCAS viruses encoding PyMT induces tumors with high penetrance. However, these tumors do not invade or metastasize to distant sites. However, if the tumors are induced in mice deficient for the p53 tumor suppressor, the tumors induced are metastatic to the lungs. Therefore, the absence of p53 does not appear to affect tumor initiation in the liver, but rather impacts tumor progression and metastasis. We have intiated gene expression microarray analyses to identify genes that mediate these effects. Preliminary data from our lab suggest that a similar effect is obtained through the deletion of the locus encoding the p16 and p19 tumor suppressor proteins.

    Current work in the lab includes:

    1. expansion of the gene expression profiling studies;
    2. evaluation of the roles of some of the candidate genes identified by the expression arrays in tumor metastasis;
    3. elucidation of the cooperating genetic alterations required for tumor induction by c-myc.

    Please also see the UMass Pancreas Program website.

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Pan D, Mao C, Quattrochi B, Friedline RH, Zhu LJ, Jung DY, Kim JK, Lewis B, Wang YX. MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun. 2014 Aug 22; 5:4725. PMID: 25145289.
      View in: PubMed
    2. Sano M, Driscoll DR, De Jesus-Monge WE, Klimstra DS, Lewis BC. Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms. Gastroenterology. 2014 Jan; 146(1):257-67. PMID: 24067880.
      View in: PubMed
    3. Jiao B, Taniguchi-Ishigaki N, Güngör C, Peters MA, Chen YW, Riethdorf S, Drung A, Ahronian LG, Shin J, Pagnis R, Pantel K, Tachibana T, Lewis BC, Johnsen SA, Bach I. Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. Mol Biol Cell. 2013 Oct; 24(19):3085-96. PMID: 23904271.
      View in: PubMed
    4. Chen YW, Chu HC. p16 Stimulates CDC42-dependent migration of hepatocellular carcinoma cells. PLoS One. 2013; 8(7):e69389. PMID: 23894465.
      View in: PubMed
    5. Wang J, Park JS, Wei Y, Rajurkar M, Cotton JL, Fan Q, Lewis BC, Ji H, Mao J. TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPa function. Mol Cell. 2013 Jul 25; 51(2):211-25. PMID: 23769673.
      View in: PubMed
    6. Huang H, Cotton JL, Wang Y, Rajurkar M, Zhu LJ, Lewis BC, Mao J. Specific requirement of Gli transcription factors in Hedgehog-mediated intestinal development. J Biol Chem. 2013 Jun 14; 288(24):17589-96. PMID: 23645682.
      View in: PubMed
    7. Appleman VA, Ahronian LG, Cai J, Klimstra DS, Lewis BC. KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. Mol Cancer Res. 2012 Sep; 10(9):1228-39. PMID: 22871572.
      View in: PubMed
    8. Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL, Klimstra DS, Zhu LJ, Simin K, Xu L, McMahon AP, Lewis BC, Mao J. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012 Apr 24; 109(17):E1038-47. PMID: 22493246.
      View in: PubMed
    9. Chen YW, Boyartchuk V, Lewis BC. Differential roles of insulin-like growth factor receptor- and insulin receptor-mediated signaling in the phenotypes of hepatocellular carcinoma cells. Neoplasia. 2009 Sep; 11(9):835-45. PMID: 19724677.
      View in: PubMed
    10. Morton JP, Klimstra DS, Mongeau ME, Lewis BC. Trp53 deletion stimulates the formation of metastatic pancreatic tumors. Am J Pathol. 2008 Apr; 172(4):1081-7. PMID: 18310506.
      View in: PubMed
    11. Chen YW, Paliwal S, Draheim K, Grossman SR, Lewis BC. p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein. Cancer Res. 2008 Jan 15; 68(2):476-82. PMID: 18199542.
      View in: PubMed
    12. Du YC, Lewis BC, Hanahan D, Varmus H. Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion. PLoS Biol. 2007 Oct 16; 5(10):e276. PMID: 17941720.
      View in: PubMed
    13. 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 Res. 2007 Oct 1; 67(19):9322-9. PMID: 17909040.
      View in: PubMed
    14. 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 Res. 2007 Aug 15; 67(16):7589-96. PMID: 17699762.
      View in: PubMed
    15. Morton JP, Lewis BC. Shh signaling and pancreatic cancer: implications for therapy? Cell Cycle. 2007 Jul 1; 6(13):1553-7. PMID: 17611415.
      View in: PubMed
    16. 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. Proc Natl Acad Sci U S A. 2007 Mar 20; 104(12):5103-8. PMID: 17372229.
      View in: PubMed
    17. Lewis BC. Development of the pancreas and pancreatic cancer. Endocrinol Metab Clin North Am. 2006 Jun; 35(2):397-404, xi. PMID: 16632101.
      View in: PubMed
    18. 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. Mol Cell Biol. 2005 Feb; 25(4):1228-37. PMID: 15684377.
      View in: PubMed
    19. 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 Dev. 2003 Dec 15; 17(24):3127-38. PMID: 14681205.
      View in: PubMed
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