Email: tleung@nccu.edu
MY RESEARCH FOCUS is to understand the mechanisms by which signaling molecules guide and pattern vascular networks during angiogenesis (formation of new blood vessel), and to exploit the therapeutic potential of chemical modulators (drug like small molecules and natural products) that will suppress cardiovascular diseases and to combat cancers.
A breakthrough in cancer biology is the discovery of angiogenesis targeting strategies to block tumor growth and metastasis. Angiogenesis plays a significant role in human cancer progression and there is a high degree of correlation between microvessel density and Gleason score, pathological stage, and patient survival. Stromal-epithelial interactions have been identified as an essential process for various types of cancer progression and metastasis. Therapeutic agents which target the crosstalk between host stroma and tumor could potentially block the progression of cancer, providing a rational strategy for co-targeting more than one process to enhance the efficacy of traditional epithelial targeting strategies in cancer management. Potential pathways of interest include those that regulate tumor-associated angiogenesis, pathways essential for cancer development and those that are associated with carcinogenesis. However, not much is known about the molecular mechanisms underlying tumor induced angiogenesis, the genes or pathways involved in progression or the tumor-stromal interactions which allow tumor progression and establishment of tumor metastases in a new location. Thus, determining the molecular mechanisms underlying tumor induced angiogenesis will enable us to target angiogenic signaling pathways regulating tumor progression.
We use zebrafish as a vertebrate model system for our analyses because of the striking similarity in protein sequences, conserved developmental processes of organogenesis, and the common appearance of pathophysiological processes between zebrafish and human. Phenotypic resemblance of zebrafish gene mutations to human cardiovascular disease as well as physiological responses to drugs exhibited in the zebrafish system provide strong arguments for its use as a model system to study human cardiovascular development and disease. In addition, zebrafish cancer model recapitulates the human disease both molecularly and pathologically. For example, zebrafish neoplasms induced by carcinogen or oncogene histologically resemble human tumors from various organs. Together with the similarity of gene-expression profiling was consistent from zebrafish tumors to human cancer, supporting the use of zebrafish as a human tumor model. Particularly relevant to my studies, zebrafish development is ex-utero, embryos are optically transparent allowing visual analysis of blood vessel development, gene knockdown technology enables the specific inhibition of genes involved in angiogenesis, transgenic fish with fluorescently labeled blood vessels are available and embryonic development is rapid allowing easy analysis of angiogenic events. In summary, the large-scale vertebrate genetics combined with chemical suppressor and enhancer screens will make the zebrafish an innovative high-throughput drug discovery tool.
Balsamo, J., Leung, T.C., Ernst, H., Zanin, M.K.B., Hoffman, S., Lilien, J. 1996. Regulated binding of a PTP1b-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of beta-catenin. J. Cell Biology 134:801-813.
Balsamo, J., Arregui, C., Leung, T.C., Lilien, J. 1998. The nonreceptor protein tyrosine phosphatase PTP1B binds to the cytoplasmic domain of N-cadherin and regulates the cadherin-actin linkage. J. Cell Biology 143:523-532.
Fekany, K., Yamanaka, Y., Leung, T.C., Sirotkin, H.I., Topczewski, J., Gates, M.A., Hibi, M., Renucci, A., Stemple, D., Radbill, A., Schier, A.F., Driever, W., Hirano, T., Talbot, W., Solnica-Krezel, L. 1999. The zebrafish bozozok locus encodes Dharma, a homeodomain protein essential for induction of gastrula organizer and dorso-anterior embryonic structures. Development 126: 1427-1438.
Li, H., Leung, T.C., Hoffman, S., Balsamo, J., Lilien, J. 2000. Coordinate Regulation of Cadherin and Integrin Function by the Chondroitin Sulfate Proteoglycan Neurocan. J. Cell Biol. 149:1275-1288.
Pathre, P., Arregui, C., Wampler, T., Kue, I., Leung, T.C., Lilien, J., Balsamo, J. 2001. PTP1B regulates neurite extension mediated by cell-cell and cell-matrix adhesion molecules. J. Neurosci. Res. 63:143-150.
Doitsidou, M., Reichman-Fried, M., Stebler, J., Koprunner, M., Dorries, J., Meyer, D., Esguerra, C.V., Leung, T., Raz, E. 2002. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111:647-659.
Leung T, Bischof J, Söll I, Niessing D, Zhang D, Ma J, Jackle H, Driever W. 2003. bozozok directly represses bmp2b transcription and mediates the earliest dorsoventral asymmetry of bmp2b expression in Zebrafish. Development 130:3639-3649.
Leung, T., Söll, I., Arnold, S., Wolf, K., Driever, W. 2003. Direct binding of Lef1 to sites in the boz promoter may mediate pre-midblastula-transition activation of boz expression. Developmental Dynamics (zebrafish special issue) 228:424–432.
Leung, T., Chen, H., Stauffer, A.M., Giger, K.E., Sinha, S., Horstick, E.J., Humbert, J.E., Hansen, C.A. and Robishaw, J.D. 2006. Zebrafish G protein g2 is required for VEGF signalling during angiogenesis. Blood 108:160-166.
Chen, H., Leung, T., Giger, K.E., Stauffer, A.M., Humbert, J.E., Sinha, S., Horstick, E.J., Hansen, C.A., Robishaw, J.D. 2007. Expression of the G protein gamma T1 subunit during zebrafish development. Gene Expression Pattern 7:574-583.
Leung, T., Humbert, J.E., Stauffer, A.M., Giger, K.E., Chen, H., Tsai, H.-J., Wang, C., Mirshahi, T., Robishaw, J.D. 2008. The orphan G protein coupled receptor 161 is required for left-right patterning. Developmental Biology 323:31-40.