Back to Search Results
Professor of Pharmacology and Physiology
Professor of Biochemistry and Molecular Medicine (Secondary)
Office Phone: 202-994-8855
Department: Pharmacology and Physiology
- BS, University of Maryland, Baltimore, 1985
- PhD, University of Maryland, Baltimore, 1990
Director, Molecular Medicine PhD Program, GWIBS
Director, Molecular Oncology PhD Concentration, GWIBS
Course Director MMED 8221, Basic Science of Oncology
Course Director MMED 8222, Molecular Oncology
Lecturer, PHAR 6201, PHAR 6202, PHAR 6207, PHAR 6208, MMED 8280, MICR 8236
The Lee laboratory has over 15 years of experience in the application of molecular, genomics, and computational approaches for elucidating genetic networks and pathways underlying disease processes, such as cancer progression (i.e. metastatic potential, epithelial-mesenchymal transition) and complex behavioral traits (i.e. drug seeking behavior).
Ion channels in solid tumor malignancies: We have developed a computational technique that iteratively applies Bayesian statistics (Probabilistic Graphical Models), global gene expression profiling in patient samples and cancer cell lines, and loss-of-function screening to model gene transcriptional networks. Based on Bayesian modeling and empirical evidence (pre-clinical animal models and clinical), we are currently investigating a number of cell surface signaling proteins for their involvement in colon, liver and prostate cancer metastasis. Two key gene families that have been identified in the cancer metastasis gene network are the voltage-gated cationic channels and ligand-gated anionic channels. Genes belonging to these families are typically associated with excitable cells such as neurons and cardiomyocytes. The functional expression of these ion channel genes in cancer cells poses the intriguing possibility of repurposing currently available therapeutics (e.g. local anesthetics, anti-epileptics, anxiolytics) as novel therapies for cancer. Our laboratory is currently investigating the utility of these drugs to inhibit cancer metastasis in xenograft mouse models.
Genomic screening for novel cell surface markers controlling EMT: The epithelial-mesenchymal transition (or EMT) is a transcriptional event, crucial in early development, that downregulates the expression of proteins characteristic of epithelial cells, such as E-cadherin and claudins, and increases the expression of proteins characteristic of mesenchymal cells, such as vimentin, N-cadherin and matrix metalloproteinases. As a consequence, cells undergoing EMT have decreased homotypic adhesion, increased motility, increased matrix degradation capability and increased resistance to apoptosis, which are properties necessary for cancer metastasis. By applying genomics and loss-of-function screening approaches, we have identified a variety of gene family members encoding cell surface proteins, intracellular signal transduction molecules and secreted factors that are associated with the regulation of EMT. We are currently focusing our efforts on two novel cell surface markers (CD99 and CD99L2; both belonging to the same gene family) that function as repressors of EMT. Immunohistochemical analysis of patient samples demonstrates that CD99 is expressed along cell membranes in normal colonic mucosal glands, but reduced in patient-matched colonic carcinomas. Both CD99 and CD99L2 have been established in our laboratory to mechanistically function as upstream transcriptional repressors of gene networks conferring EMT, thus portending a potential novel therapeutic role for antibody ligation of CD99 in the control of colon cancer progression.
Cancer health disparities: There are striking population (race) disparities in prostate cancer risk and survival outcome borne out of current health statistics data. This is particularly evident between African Americans (AA) and their Caucasian American (CA) counterparts. Epidemiologic studies have shown that higher mortality and recurrence rates for prostate cancer are still evident in AA men even after adjustment for socioeconomic status, environmental factors and health care access. Thus, it is likely that intrinsic biological differences account for some of the cancer disparities. Our overarching hypothesis is that the biological component of prostate cancer health disparities is due, in part, to population-dependent differential splicing of oncogenes and tumor suppressor genes in cancer specimens. The application of genomic approaches has identified splice variants in AA specimens, but absent in CA specimens, encoding more aggressive oncogenic proteins, thereby producing a more cancerous phenotype.
Genomics of drug seeking behavior in animal models: C57BL/6J inbred mice but not DBA/2J animals readily self-administer opioids and develop tolerance to the analgesic effects of opioids. By applying genomics to the study of behavior genetics in inbred mouse strains, the Lee laboratory in collaboration with the Elmer group (University of Maryland) have identified a number of transcriptional regulators, microRNA processing enzymes, and microRNAs participating in opioid self-administration and tolerance behaviors. Methodologies have been developed to validate causal links between candidate genes and behavior by exploiting lentivirus-containing shRNAs delivered in vivo to specific brain regions of inbred strains. By targeting Dicer1 (encoding a microRNA processing enzyme) for knockdown in the prefrontal cortex via shRNA, C57BL/6J targeted animals exhibit decreased development of analgesic tolerance and in fact show signs of increased analgesia compared to control mice. These findings portend new research avenues directed at developing drugs to target the microRNA pathway in order to ameliorate the development of analgesic tolerance, thereby reducing the need to escalate dosing of opioids for chronic pain management in the clinical setting. Ongoing collaborations include Dr. David Perry at GWUMC to study the genomics of nicotine addiction, and Drs. Thomas Maynard (GWUMC) and Greg Elmer to study the effects of conditional Dicer1 knock-out in mice and opioid drug seeking behavior.
Centers and Institutes
GW Institute for Biomedical Sciences
View publications by this faculty member.
Henderson, B. Lee N.H., Shen H., and Stefánsson K. (2012) The influence of race and ethnicity on the biology of cancer. Nature Review Cancer (in press).
Tapocik J.D., Luu T.V., Mayo C.L., Wang B.-D., Doyle E., Lee A.D., Lee N.H. * and Elmer G.I.* (2012) Neuroplasticity, axonal guidance and microRNA genes play an essential role in morphine self-administration behavior. Addiction Research (in press). *Corresponding authors.
Makhoul R., Schwartz A.M., Williams R., and Lee N.H. (2011) Paranuclear dot-like immunoreactivity for CD99: presence in colonic adenomas and adenocarcinomas. American Journal of Surgical Pathology 35: 1749-1750.
Riz I., Hawley T.S. Luu T.V., Lee N.H.* and Hawley R.G.* (2010) TLX1 and Notch coregulate transcription in T-ALL cells. Molecular Cancer 9:181 *Corresponding authors.
House C.D., Vaske C.J., Schwartz A.M., Obias V., Frank B., Luu T., Sarvazyan N., Strausberg R.L., Hales T.G., Stuart J.M. and Lee N.H. (2010) Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. Cancer Research 70: 6957-6967.
Wang B.-D., Kline C.L.B., Pastor D.M., Olson T.L., Frank B., Luu T., Sharma A.K., Robertson G., Weirauch M.T., Patierno S.R., Stuart J.M., Irby R.B., Lee N.H. (2010) Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of the NFkB and microRNA pathways. Molecular Cancer 9: 98.
Kwabi-Addo B., Wang S., Chung W., Jelinek J., Patierno S.R., Wang B.-D., Lee N.H., Issa J.-P., Ittmann M. (2010) Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian males. Clinical Cancer Research 16: 3539-3547.
Vaske C.J., House C., Frank B., Yeang C.-H., Lee N.H.* and Stuart J.M.* (2009) A factor graph nested effects model to identify networks from genetic perturbations. PLOS Computational Biology 5: e1000274. *Corresponding authors.
Tapocik J.D., Letwin N.E., Kafkafi N., Mayo C., Frank B., Luu T.V., Achinike O., House C., Williams R., Elmer G.I. *, and Lee N.H. * (2009) Identification of candidate genes and gene networks specifically associated with analgesic tolerance to morphine. Journal of Neuroscience 29: 5295-5307. *Corresponding authors.
Malek R.L., Wang H.-y., Kwitek A., Green A.S., Luu T.V., Veratti K., Letwin N., Cahill L., Sajadi H., Borchardt G., Fu X., Sultana R., Tsai J., Howe E., Saeed A., Thiagarajan M., White J., Currier T., Salzberg S.L., Quackenbush J., Jacob H.J. and Lee N.H. (2006) Physiogenomic resources for rat models of heart, lung and blood disorders. Nature Genetics 38: 234-239.
Industry Relationships and Collaborations
This faculty member (or a member of their immediate family) has reported a financial interest with the health care related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.