Xiuwei Yang, Ph.D.
Assistant Professor
Dept. of Zoology, University of Manitoba, Winnipeg, Manitoba, Canada 1994
Office: MN-352 Chandler Medical Center (0298)
Lab: MS-366; (859) 323-0571
Tel: (859) 323-1996
Research Interests
Our laboratory is interested in understanding how tumor cells or cancer stem cells communicate with their surrounding microenvironments. Tumor-microenvironment interactions are critical in multiple aspects of human cancer, ranging from tumor initiation and growth to motility, invasion, trafficking and metastasis. Situated at the tumor-microenvironment interface are two crucial sets of cell surface molecules, cell adhesion receptors (e.g., integrins and cadherins), and oncogenic receptor tyrosine kinases (e.g., members of ErbB family). During human carcinogenesis these receptors act in concert to mediate tumor cell adhesion, motility, proliferation and survival. In addition, these molecules are the driving forces behind tumor dissemination and metastasis, particularly at the stages of trafficking through lymphatic or blood stream (intravasation and extravasation) and re-colonization at secondary organs or tissues. More recently, subsets of integrins have also been linked to the dynamics and malignancy of cancer stem cells.
The main focus of our research is to elucidate the molecular and cellular roles of CD151-laminin-binding integrins (α3β1, α6β1, α6β4, α7β1) protein complexes and their signaling cross-talk with ErbB receptors at various stages of human breast cancer. While the roles of ErbB receptor kinases are well recognized in human cancer, laminin-binding integrins have only recently been implicated in human epithelia-origin cancers, particularly breast and skin cancer. CD151, a member of the tetraspanin protein family, strongly and directly associates with laminin-binding integrins via a critical extracellular protein interaction site. Our recent work has demonstrated a strong relevance of CD151 to human breast cancer: i) A significant elevation in CD151 expression in high grade mammary tumors, regardless of subtype ii) Ablation of CD151 via RNA interference led to a considerable delay in ectopic mammary tumor growth in nude mice iii) CD151 removal severely impaired tumor cell attachment, migration and invasion iv) Laminin-binding integrin-dependent signaling through focal adhesion kinase (FAK), Lck, and Rac1 was markedly defective in the absence of CD151 v) The ablation of CD151 protein disrupted the molecular neighborhood of laminin-binding integrins and their signaling cross-talk with ErbB receptors.
Our ongoing work endeavors to dissect the 1) in vivo effects of CD151 on spontaneous tumor formation metastasis through the use of mouse genetic tumor models and gene-targeted mice 2) impact of disrupting CD151 and its associated complexes on the motility and invasiveness of tumor cells and their other surrounding cells, such as fibroblasts, by using a real-time imaging approach and genetic manipulation 3) links between CD151-integrin complexes and the dynamics and malignancy of human cancer stem cells 4) impact of adhesion molecules on anti-cancer drug resistance, particularly those used for targeting oncogenic receptors kinases 5) molecular organization and palmitoylation of cell surface protein complexes.
Our long-term projects involve the application of proteomic, genomic and immunology-based technologies to human cancer treatment. More specifically, we strive to uncover biomarkers and novel therapeutic targets for human epithelia-origin cancers. We are also interested in disrupting tumor progression by developing immunology-based agents to block critical surface receptors on tumor cells, which would provide alternative therapies or adjuvant drugs for treating human cancers.
Selected Publications
Xiuwei H. Yang, Rossen Mirchev, Xinyu Deng, Patrick Yacono, Helen L. Yang, David E. Golan, and Martin E. Hemler, 2012. CD151 restricts α6 integrin diffusion mode. J Cell Sci. In press (PMID: 22328509)
Yang XH, Flores LM, Li Q, Zhou P, Xu F, Krop IE, Hemler ME., 2010. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists. Cancer Res. 2010 Mar 15;70(6):2256-63. Epub 2010 Mar 2
Sharma, C., Yang, X. and Hemler, M.E., 2008. DHHC2 affects palmitoylation, stability and functions of tetraspanins CD9 and CD151. Molecular Biology of the Cell ,19: 3415-3425.
Yang, X. *, Richardson, A. L. , Torres-Arzayus, M., Zhou, P., Sharma, C., Andzelm, M.M, Strongminger, J.A., Brown, M. and Hemler, M.E., 2008. CD151 accelerates breast cancer progression by regulating alpha 6 integrin function, signaling, and molecular organization. Cancer Research, 68: 3204-13 (*: Co-corresponding author).
Kovalenko OV, Yang, X. and Hemler ME. 2007. A novel cystine crosslinking method reveals a direct association between claudin-1 and tetraspanin CD9. Molecular and Cellular Proteomics, 6:1855-1867.
Yang, X., Kovalenko OV, Kolesnikova TV, Andzelm MM, Rubinstein E, Strominger JL, Hemler ME. 2006. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. Journal of Biological Chemistry 281: 12976-85
Yang, X., Kovalenko, O.B., Stipp C., and Hemler, M.E. 2004. Palmitoylation supports assembly and function of integrin-teraspanin complexes. Journal of Cell Biology 167:1231
Kovolenco, O., Yang, X., Kolesnikova, T. and Hemler, M.E. 2004. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine available for crosslinking. Biochemical Journal 377: 407-17.
Hemler, M.E., Yang, X., Kovalenko, O.V., Song, H., Kazarov, A.R., Kolesnikova, T., and Stipp, C.S. 2003. Tetraspanin functions and microdomain organization. In: International Falk Workshop, Cell adhesion molecules in health and disease. Lancaster, UK: Kluwer Academic Publishers, Ch. 2, 26-35.
Yang, X., Claass, C., Kraeft, S., Chen, L.B., Wang, Z., Kreidberg, J.S., and Hemler, M.E. 2002. Palmitoylation of tetraspanin proteins: Modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology. Molecular Biology of the Cell 13: 767-781.
Kazarov, A.R., Yang, X., Stipp, C.S., Seghl, B. and Hemler, M.E. 2002. An extracellular site on tetraspanin CD151 determines α3 and α6 integrin-dependent cellular morphology. Journal of Cell Biology, 158: 1299-1309.
Zhang, X.A., Kazarov, A.R., Yang , X., Bontrager,A.L., Stipp, C.S., and Hemler, M.E. 2002. Function of the tetraspanin CD151-α6β1 integrin complex during cellular morphogenesis. Molecular Biology of the Cell 13: 1-11.
Yang* , X., Wei*, Y., Liu, Q., Wilkins, J.A., and Chapman H.A. 1999. A Role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. Journal of Cell Biology 144: 1285-1294. * Co-first authors
Waltz, D, Fujita, R., Yang, X., Natkin, L., Zhuo, S., Gerard, C.J., Rosenberg, S., and Chapman, H.A. 2000. Nonproteolytic role for the urokinase receptor in cellular migration in vivo. American Journal of Respir Cell Mol Biol. 22: 316-22.
Mohapatra, S., Yang, X., Wright, J.A., Turley, E.A. and Greenberg, A.H. 1996. Soluble hyaluronan receptor RHAMM induces mitotic arrest and cell death by suppressing Cdc2 expression. Journal of Experimental Medicine 183: 1663-1668.
Hall, C.L., Yang, B., Yang, X., Zhang, S., Turley, M., Samuel, S., Lange, L., Wang, C., Curpen, G.D., Savani, R.C., Greenberg, A.H. and Turley, E.A.1995. Over-expression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82: 19-28.