Center for Matrix Biology - Vanderbilt University and Medical Center

Jin Chen, M.D., Ph.D.
Associate Professor in the Department of Medicine

	Office Address:	A-4323 MCN
	Mailing Address:	A-4323 MCN Nashville, TN 2363
	Lab address:	A-4323 Medical Center North
	Phone:	615-343-3819
	FAX:	615-343-7392
		email \| website

Secondary appointment in the Cancer Biology department.
Secondary appointment in the Cell and Developmental Biology department.

Research Summary

Our major focus has been to characterize the role of a new family of receptor tyrosine kinase (RTK), the Eph receptors and their ligands ephrins, in cancer metastasis and tumor angiogenesis. Our approach involves a combination of oncogenomics and proteomics, confocal microscopy and imaging, transgenic and knock out animal models, and traditional cell biology and biochemistry techniques.

Eph RTKs and their ligands are elevated in tumor tissues and expression of these molecules is associated with degrees of tumor malignancy. In particular, EphA2 receptor plays critical roles in both tumor cells and tumor blood vessels. Our laboratory demonstrated that epithelial EphA2 is required for cell proliferation and tumor initiation. We also showed that vascular endothelial EphA2 promotes tumor progression through angiogenesis. As EphA2 regulates both tumor cells and host microenvironment, it is a good target for cancer therapy. Several anti-EphA2 agents have been developed and some of those are under clinical trials.

Recently, Eph receptors were discovered to be both tumor promoters and tumor suppressors. We are currently investigating molecular mechanisms that are involved in converting Eph receptor function from tumor inhibition to tumor promotion. We are also dissecting the role of ephrin-A1/EphA2 in tumor-endothelial interaction during tumor metastasis. Through oncogenomic and proteomic analysis, multiple candidate genes and interacting proteins were identified. These molecules will be tested for their roles in EphA2-mediated tumorigenesis, angiogenesis, and metastatic progression.

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Associated initiative(s):

Angiogenesis

Tumor Microenvironment

Career opportunities:
Postdoctoral Position Available

Selected Publications

» Vaught, D, Chen, J, Brantley-Sieders, DM Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase Mol Biol Cell 2009. 20:2572-81

» Brantley-Sieders, DM, Zhuang, G, Vaught, D, Freeman, T, Hwang, Y, Hicks, D, Chen, J Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo Mol Cancer Res 2009. 7:615-23

» Chen, J, Zhuang, G, Frieden, L, Debinski, W Eph receptors and Ephrins in cancer: common themes and controversies Cancer Res 2008. 68:10031-3

» Fang, WB, Ireton, RC, Zhuang, G, Takahashi, T, Reynolds, A, Chen, J Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism J Cell Sci 2008. 121:358-68

» Fang, WB, Brantley-Sieders, DM, Hwang, Y, Ham, A, Chen, J Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase J Biol Chem 2008. :

» Brantley-Sieders, DM, Zhuang, G, Hicks, D, Fang, WB, Hwang, Y, Cates, JM, Coffman, K, Jackson, D, Bruckheimer, E, Muraoka-Cook, RS, Chen, J The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling J Clin Invest 2008. 118:64-78

» Vaught, D, Brantley-Sieders, DM, Chen, J Eph receptors in breast cancer: roles in tumor promotion and tumor suppression Breast Cancer Res 2008. 10:217

» Zhuang, G, Hunter, S, Hwang, Y, Chen, J Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation J Biol Chem 2007. 282:2683-94

» Brissova, M, Shostak, A, Shiota, M, Wiebe, PO, Poffenberger, G, Kantz, J, Chen, Z, Carr, C, Jerome, WG, Chen, J, Baldwin, HS, Nicholson, W, Bader, DM, Jetton, T, Gannon, M, Powers, AC Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function Diabetes 2006. 55:2974-85

» Brantley-Sieders, DM, Fang, WB, Hwang, Y, Hicks, D, Chen, J Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice Cancer Res 2006. 66:10315-24

» Chen, J, Hicks, D, Brantley-Sieders, D, Cheng, N, McCollum, GW, Qi-Werdich, X, Penn, J Inhibition of retinal neovascularization by soluble EphA2 receptor Exp Eye Res 2006. 82:664-673

» Hunter, SG, Zhuang, G, Brantley-Sieders, D, Swat, W, Cowan, CW, Chen, J Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis Mol Cell Biol 2006. 26:4830-42

» Ireton, RC, Chen, J EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics Curr Cancer Drug Targets 2005. 5:149-57

» Brantley-Sieders, DM, Fang, WB, Hicks, DJ, Zhuang, G, Shyr, Y, Chen, J Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression FASEB J 2005. 19:1884-6

» Fang, WB, Brantley-Sieders, DM, Parker, MA, Reith, AD, Chen, J A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis Oncogene 2005. :

» Brantley-Sieders, D, Parker, M, Chen, J Eph receptor tyrosine kinases in tumor and tumor microenvironment Curr Pharm Des 2004. 10:3431-42

» Brantley-Sieders, Dana M, Caughron, Justin, Hicks, Donna, Pozzi, Ambra, Ruiz, Joseph C, Chen, Jin EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation J Cell Sci 2004. 117:2037-49

» Parker, Monica, Roberts, Richard, Enriquez, Miriam, Zhao, Xia, Takahashi, Takamune, Pat Cerretti, Douglas, Daniel, Tom, Chen, Jin Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway Biochem Biophys Res Commun 2004. 323:17-23

» Brantley-Sieders, Dana M, Chen, Jin Eph receptor tyrosine kinases in angiogenesis: from development to disease Angiogenesis 2004. 7:17-28

» Cheng, Nikki, Brantley, Dana, Fang, Wei Bin, Liu, Hua, Fanslow, William, Cerretti, Douglas Pat, Bussell, Katrin N, Reith, Alastair, Jackson, Dowdy, Chen, Jin Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors Neoplasia 2003. 5:445-56

» Brantley, Dana M, Cheng, Nikki, Thompson, Erin J, Lin, Qing, Brekken, Rolf A, Thorpe, Philip E, Muraoka, Rebecca S, Cerretti, Douglas Pat, Pozzi, Ambra, Jackson, Dowdy, Lin, Charles, Chen, Jin Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo Oncogene 2002. 21:7011-26

» Muraoka, Rebecca S, Dumont, Nancy, Ritter, Christoph A, Dugger, Teresa C, Brantley, Dana M, Chen, Jin, Easterly, Evangeline, Roebuck, L Renee, Ryan, Sarah, Gotwals, Philip J, Koteliansky, Victor, Arteaga, Carlos L Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases J Clin Invest 2002. 109:1551-9

» Cheng, Nikki, Brantley, Dana M, Chen, Jin The ephrins and Eph receptors in angiogenesis Cytokine Growth Factor Rev 2002. 13:75-85

» Cheng, Nikki, Brantley, Dana M, Liu, Hua, Lin, Qin, Enriquez, Miriam, Gale, Nick, Yancopoulos, George, Cerretti, Douglas Pat, Daniel, Thomas O, Chen, Jin Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis Mol Cancer Res 2002. 1:2-11

» Huynh-Do, Uyen, Vindis, C??cile, Liu, Hua, Cerretti, Douglas Pat, McGrew, Jeffrey T, Enriquez, Miriam, Chen, Jin, Daniel, Thomas O Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis J Cell Sci 2002. 115:3073-81

» Cheng, N, Chen, J Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism J Biol Chem 2001. 276:13771-7

» Chen, J, Ruley, H E An enhancer element in the EphA2 (Eck) gene sufficient for rhombomere-specific expression is activated by HOXA1 and HOXB1 homeobox proteins J Biol Chem 1998. 273:24670-5

» Chen, J, Nachabah, A, Scherer, C, Ganju, P, Reith, A, Bronson, R, Ruley, H E Germ-line inactivation of the murine Eck receptor tyrosine kinase by gene trap retroviral insertion Oncogene 1996. 12:979-88