 Nancy Thompson, PhD
COBRE CCRD Deputy Director
Professor of Medicine and Pathology
Nancy Thompson, PhD, is a professor of medicine and pathology at Brown University and a research oncologist in the division of medical oncology at Rhode Island Hospital. She is the previous director of the multi-departmental Brown University graduate program in pathobiology, which provides doctorate level training in cancer biology, environmental pathology, and immunology and infectious diseases. She is the principal investigator of a U.S. Department of Education Graduate Assistance in Areas of National Need (GAANN) training grant in pathobiology, a National Institutes of Health (NIH) RO1 grant and an American Institute for Cancer Research grant. She received her research training at Rutgers University, Brown University and at the NIH. Thompson's research expertise includes hepatocarcinogenesis and injury, gene expression and the regulation and role of heterdimeric glycoprotein transporters in cell activation and cancer. The author of more than 50 research articles and book chapters, she has served on several NIH review panels and reviewed manuscripts for multiple journals.
Research Focus: Molecular Mechanisms in Carcinogenesis & Oncoinjury Related Gene Expression
This interactive and collaborative research program seeks to determine the relationship and regulation of "new" genes identified in tumor cells to the neoplastic process and how these may differ from their normal physiological roles.
Two genes (with multiple names reflecting their study now in several laboratories) identified and under intense scrutiny in our lab, TuAg.1/Tage4 and TA1/E16/LAT-1, were discovered in the rat liver system, but have been found to have close relatives expressed in human cancer. Long term objectives of this research are to define molecular mechanisms of neoplasia using hepatic model systems and to explore their relation to normal injury-response and developmental pathways. In study of these genes, our group is committed to furthering basic understanding of disease processes, as well as seeking clinical applications to benefit patients.
TA1/E16/LAT-1 is a hydrophobic integral membrane protein recently found to be the light chain of the CD98 heterodimer, a molecule associated with amino acid transport, cell activation and integrin activation. The light chain is highly conserved and homologs have been found in distant organisms including parasites and frogs. The rat and human molecules are 95 percent identical. Our studies demonstrate that TA1/E16/LAT-1 expression is up regulated in rat and human primary cancers and cell lines while CD98 heavy chain expression appears to be constitutive. TA1 expression is altered in hepatic cells in response to the amino acid availability. The mechanism responsible for this response is currently under investigation. Studies in progress are examining our key hypothesis that the CD98 complex, particularly TA1/E16/LAT-1 light chain provides an adaptive advantage to tumor cells, supporting higher metabolic demands, particularly under conditions of nutrient stress.
TuAg.1 is a cell surface glycoprotein originally discovered on the basis of its differential expression in rat hepatocarcinogenesis. It is a member of the immunoglobulin (Ig) superfamily, closely related to a gene cloned from rat colon and mammary carcinomas, and has an undefined human homolog with apparent expression in gastrointestinal carcinomas. It is expressed in fetal liver and liver injury as well.
We hypothesize that like other Ig family members, TuAg.1 plays a recognition and signaling function and that its expression conveys an adaptive advantage in liver oncoinjury. TuAg.1 expression may result from, or alternatively, result in, alterations in cellular interactions or polarity that are common between carcinogenesis, development and injury response. In this regard, TuAg.1 may be a relay for environmental cues. Strategies to define the molecules with which it interacts, cancer phenotypes to which it contributes and cellular processes in which it acts are underway.
Selected Publications
Lim, Y.P., Fowler, L.C., Hixson, D.C., Wehbe, T. and Thompson, N.L. TuAg.1 is the liver isoform of the rat colon tumor-associated antigen, pE4, and a member of the immunoglobulin-like supergene family. Cancer Res., 56:3934-3940, 1996.
Chapman, L., Sang, J., Lin, S.H., Hixson, D.C. and Thompson, N.L. Cloning of cDNAs from a mammalian expression library by a direct selection-amplification method. Mol. Biotech., 5:77-83,1996.
Wolf, D.A., Wang, S., Panzica, M.A., Bassily, N.H. and Thompson, N.L. Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to S. mansoni amino acid permease and C. elegans gene products. Cancer Res. 56:5012-5022, 1996.
Shultz, V.D., Degli Esposti, S., Panzica, M.A., Abraham, A., Finch, P. and Thompson, N.L. Expression of TA1, a rat oncofetal cDNA with homology to transport-associated genes, in carbon tetrachloride-induced liver injury. Pathobiology, 65:14-25, 1997.
Mannion, B.A., Kolesnikova, T.V., Lin, S.H., Wang, S., Thompson, N.L., and Hemler, M.E. The light chain of CD98 is identified as E16/TA1 Protein. J. Biol. Chem. 273:33127-33129, 1998.
Shultz, V.D., Campbell, W., Karr, S., Hixson, D.C. and Thompson, N.L. TA1 oncofetal rat liver cDNA and putative amino acid permease: temporal correlation with c-myc during acute liver injury and variation of RNA levels in response to amino acids in hepatocyte cultures. Toxicol. and Applied Pharmacol., 154:84-96, 1999.
Campbell, W. A., Sah, D.E., Albina J.E., Coleman, W.B., and Thompson, N.L.. TA1/LAT-1/CD98 light chain and system L activity, but not 4F2/CD98 heavy chain, respond to arginine availability in rat hepatic cells: loss of response in tumor cells. J. Biol. Chem., 275:5347-5354, 2000.
Diah, S.K., Padbury, J.F., Campbell, W.A., Britt, D., and Thompson, N.L. Molecular cloning of the rat TA1/LAT-1/CD98 light chain gene promoter. Biochimica et Biophysica Acta 1518:267-270, 2001.
Campbell, W.A., and Thompson, N.L. Overexpression of LAT-1/CD98 light chain is sufficient to increase system L amino acid transport activity in mouse hepatocytes but not fibroblasts. J. Biol. Chem. 276:16877-16884, 2001.
One Hoppin Street • Providence, RI 02903
Phone: 401-444-7237 • email: AGarcia3@lifespan.org
|
