Shi-Yuan Cheng, Ph.D. Associate Professor
Ph.D. The Ohio State University, Columbus, Ohio, 1992
Email: chengs@upmc.edu
Dr. Cheng's research interests focus on molecular mechanisms of cell motility, invasion, metastases and angiogenesis: the roles of growth factors, small Rho GTPases, guanine exchange factors and their modulators. We are also interested in developing novel approaches for cancer therapies.
Cancer Cell Invasion and Metastasis, the spread of tumor cells from primary tumor sites to nearby tissues or distant organs, is the major cause of death in patients with cancers. Cell invasion is a multi-step process involving attachment of invading tumor cells to the extracellular matrix (ECM), disruption of ECM components, cell movement and invasion into surrounding tissues, survival and subsequent growth. Cancer metastasis is also involved in cell intravasation into blood circulation, travel to distant organ sites where tumor cells extravasate out of vessels, survive in the new microenvironment and establish secondary tumors. Acquisition of migratory/invasive properties by various cells involves in activation of multiple signaling pathways. Among these pathways, small Rho GTPases such as Rac1, Cdc42 and Rho A and their regulators have taken the central stages in modulating cell motility and invasion.
Small Rho GTPases and guanine exchange factors in glioma cell invasion:
A primary research interest in our laboratory is to understand how malignant human glioma cells invade into nearby normal brain structures. In the clinic, the intrinsic infiltration of single glioma cells into brain parenchyma renders these cancers resistant to current treatments of surgical removal in combination with radiation, chemo- and immuno-therapies. Our recent genome-wide DNA array analyses of glioma invasion models identified several molecules that modulate the function of Rac1 and Cdc42 and their regulators such as guanine nucleotide exchange factors (GEF) critical for cell motility/invasion. One of such molecules is a bipartite GEF for Rac1, ELMO1-Dock180 to be critical in promoting glioma cell invasion in vitro and in vivo (Cancer Res. 2007, in press). Current projects study signaling pathways that regulate GEFs including ELMO1-Dock180, small GTPases Rac1 and additional modulators of GEFs or small GTPases stimulating glioma cell motility/invasion.
Signaling pathways that promotes cell motility and survival in breast cancer metastasis:
We recently showed that that angiopoietin-2 (Ang2) induces tumor metastasis of human MCF-7 breast cancer cells, a poorly metastatic cell line, to become metastatic through integrin-integrin linked kinase (ILK)-Akt/GSK 3 be??-Snail-E-cadherin pathway (Cancer Res. 2007, 67:4254-4263) and promotes breast cancer survival in the lung (target organ) through up-regulating Bcl-2. Interesting, Ang2-activated signaling pathways are similar to that of several other breast cancer metastatic promoter such as Her2 overexpression in breast cancer cells. We are currently investigating involvement of various signaling pathways such as small Rho GTPases, GEFs and their regulators that promote breast cancer cell motility, and modulators of Bcl-2 enhancing cell survival in distant organs leading to breast cancer metastasis.
Angiogenesis and anti-tumor therapies:
Vascular endothelial growth factor (VEGF) family and their receptors are the major angiogenic factors. We demonstrated that VEGF-A isoforms, VEGF121, VEGF165 and VEGF189, displayed distinct activities in different anatomic sites. Currently, we are investigating the involvement of GEFs and small Rho GTPases in VEGF-stimulated endothelial cell motility and angiogenesis using in vitro and ex vivo model systems. In addition, in collaboration with Dr. Erik Weiner, a MRI expert at our Cancer Institute, we are also evaluating therapeutic effects on glioma angiogenesis in vivo using clinically approved anti-tumor drugs such as temozolomide and ZD6474, an inhibitor of VEGFR and EGFR coupled with MRI imaging with novel contrast agents that specifically target blood vessels.
Trainees will utilize the following techniques that are routinely used in the laboratory:
Cell culture, transient and stable transfection, gene expression including tet-inducible system, plasmid, retroviral, lentiviral, AAV expression, siRNA inhibition, PCR and real-time PCR, cDNA cloning, subcloning, site-direct mutagenesis, DNA array analyses, gel electrophoresis, cell migration, invasion and proliferation, zymographic assays, protein expression in bacteria and mammalian cell culture, protein purification, protein-receptor binding assays, immunoprecipitation, Western blot, ELISA, immunofluorescence, FACS sorting and analyses, tumor xenograft animal model, stereotactic brain implantation, tissue processing, immunohistochemistry and microscopic imaging.
Recent Publication
Guo, P., Fang, Q., Tao, H.-Q., Schafer, A. C., Fenton, B. M., Ding, I., Hu, B. and Cheng, S.-Y. (2003) "Overexpression of VEGF by MCF-7 Breast Cancer Cells Promotes Estrogen-independent Growth in vivo." Cancer Res. 63, 4684-4691.
Hu, B., Guo, P., Fang, Q., Tao, H.-Q., Schafer, A. C., Wang, D.-G., Su Huang, H.-J., Gunji, Y., Nagane, M., Nishikawa, R., Alitalo, K., Cavenee, W. K. and Cheng, S.-Y. (2003) "Angiopoietin-2 Induces Human Glioma Invasion through the Activation of Metalloprotease-2." Proc. Natl Acad. Sci. USA. 100, 8904-8909
Cackowski, F.C., Xu, L., Hu, B. and Cheng, S.-Y. (2004) "Identification of Two Novel Alternatively Spliced Neuropilin-1 Isoforms" Genomics, 84, 82-94
Jarzynka, M. J. and Cheng, S.-Y. (2005) Platelet-derived growth factor-B (PDGF-B) and pericyte recruitment. Microvascular Research: Biology and Pathology, Elsevier Science & Technology Books, pp117-120. (invited review).
Guo, P., Imanishi, Y., Cackowski, F.C., Jarzynka, M., Tao, H.-Q., Hirose, T., Nishikawa, R., Hu, B. and Cheng, S.-Y. (2005) "Up-regulation of Angiopoietin-2, Metalloprotease-2, Membrane Type 1 Metalloprotease, and Laminin 5 Gamma 2 in Invading Glioma Cells Correlates with the Invasiveness of Human Gliomas." Am. J. Pathol., 166:879-890.
Hu, B., Jarzynka, M., Guo, P., and Cheng, S.-Y. (2006) "Angiopoietin-2 Stimulates Metalloprotease-2 Expression and Glioma Cell Invasion through alpha v and beta 1 Integrin and FAK Signaling Pathway" Cancer Res., 66(2)775-783.
Jarzynka, M. J., Guo, P., Bar-Joseph, I., Hu, B. and Cheng, S.-Y. (2006) "Estrogen and Nicotine Promotes Human Lung Cancer Angiogenesis and Tumor Growth" Int. J. Oncol., 28:337-344.
De Clerck, Y.A., Weissman, B.E., Yu, D., Parsons, R., Bar-Eli, M., Roy-Burman, P., Seewaldt, V.L., Cress, A., Languino, L.R., .Batra, S.K., Tang, C.K., Sheng, S., Chen, W.-T., Chellappan, S., Cheng, S.-Y., Ladisch, S., McCarthy, J.B., Coussens, L.M., Cohen, M.B. (2006) "Tumor Progression and Metastasis from Genetic to Microenvironmental Determinants " Cancer Biol. & Therapy, 5(12)1588-1599.
Imanishi, Y., Hu, B., Jarzynka, M. J., Guo, P., Bar-Joseph, I., and Cheng, S.-Y. (2007) "Angiopoietin-2 Stimulates Human Breast Cancer Cell Metastasis through the 5 1 Integrin-mediated Pathway", Cancer Res., 67(9) 4254-4263.
Hu, B., Guo, P., Imanishi, Y., Bar-Joseph, I., Jarzynka, M. J., Mikkelsen, T., Bogler, O., Hirose, T., Nishikawa, R., and Cheng, S.-Y. (2007) "Neuropilin-1 Promotes Glioma Progression through Potentiating the Activities of the HGF/c-Met Pathway", Oncogene, 26(38):5577-5586 [Epub ahead of print on March 19].
Jarzynka M.J., Hu B., Bar-Joseph, I., Gu W., Hirose T., Tosello-Trampont, A.-C., Ravichandran K. S., Nishikawa R. and Cheng, S.-Y. (2007). "Dock180 and ELMO1, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Glioma Cell Migration and Invasion." Cancer Res., 67(15) 7203-7211.
Gong, H.-B., Guo, P., Zhai, Y., Zhou, J., Uppal, H., Jarzynka M.J., Song, W., Cheng, S.-Y., and Xie, W., (2007) "Estrogen Deprivation and Inhibition of Breast Cancer Growth in vivo through Activation of the Orphan Nuclear Receptor LXR." Mol. Endocrinol., 2007; 21(8) 1781-1790 [Epub ahead of print on May 29].
