Jin Chen, M.D., Ph.D.
Professor of Medicine (Rheumatology)
Professor of Cell and Development Biology
Professor of Cancer Biology
Vanderbilt University Medical Center
T-3219 Medical Center North
Nashville, TN 37232-2681
To investigate the role of Eph receptor tyrosine kinases and their ligands (ephrins) in tumor angiogenesis, tumor metabolism, and cancer stem cells, and to develop inhibitors targeting EphA2 receptor in cancer.
Our major focus has been to characterize the role of Eph receptor tyrosine kinases and their ligands, ephrins, in tumor metabolism, 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 dysregulated in tumor tissues and expression of these molecules is associated with clinical outcome of various cancer types. 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 we are testing selective small molecule Eph receptor kinase inhibitors. Current projects in the lab include:
1. Role of ephrin-A1, the ligand for EphA2 RTK, in tumor metabolism in breast cancer.
2. EphA2 in K-Ras and TKI-resistant EGFR mutant lung cancer and cancer stem cells.
3. Dissecting opposing roles of EphA2 and EphA3 in lung cancer.
4. Regulation of angiocrine signaling in tumor progression, metastasis, and stem cell function.
- Chen, J, Song, W, Amato, K Eph receptor tyrosine kinases in cancer stem cells. Cytokine Growth Factor Rev, 2014.
- Amato, KR, Wang, S, Hastings, AK, Youngblood, VM, Santapuram, PR, Chen, H, Cates, JM, Colvin, DC, Ye, F, Brantley-Sieders, DM, Cook, RS, Tan, L, Gray, NS, Chen, J Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest, 124(5), 2037-49, 2014.
- Song, W, Ma, Y, Wang, J, Brantley-Sieders, D, Chen, J JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res, 74(9), 2444-54, 2014.
- Boissier, P, Chen, J, Huynh-Do, U EphA2 Signaling Following Endocytosis: Role of Tiam1. Traffic, 14(12), 1255-71, 2013.
- Zhuang, G, Song, W, Amato, K, Hwang, Y, Lee, K, Boothby, M, Ye, F, Guo, Y, Shyr, Y, Lin, L, Carbone, DP, Brantley-Sieders, DM, Chen, J Effects of Cancer-Associated EPHA3 Mutations on Lung Cancer. J Natl Cancer Inst, 2012.
- Funk, SD, Yurdagul, A, Albert, P, Traylor, JG, Jin, L, Chen, J, Orr, AW EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. Arterioscler Thromb Vasc Biol, 32(3), 686-95, 2012.
- Chen, J Regulation of tumor initiation and metastatic progression by eph receptor tyrosine kinases. Adv Cancer Res, 1141-20, 2012.
- Hahn, AS, Kaufmann, JK, Wies, E, Naschberger, E, Panteleev-Ivlev, J, Schmidt, K, Holzer, A, Schmidt, M, Chen, J, KÃ¶nig, S, Ensser, A, Myoung, J, Brockmeyer, NH, StÃ¼rzl, M, Fleckenstein, B, Neipel, F The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi''s sarcoma-associated herpesvirus. Nat Med, 2012.
- Rao, M, Song, W, Jiang, A, Shyr, Y, Lev, S, Greenstein, D, Brantley-Sieders, D, Chen, J VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PLoS One, 7(10), e46281, 2012.
- Lee, K, Nam, KT, Cho, SH, Gudapati, P, Hwang, Y, Park, DS, Potter, R, Chen, J, Volanakis, E, Boothby, M Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med, 209(4), 713-28, 2012.
- Brantley-Sieders, DM, Jiang, A, Sarma, K, Badu-Nkansah, A, Walter, DL, Shyr, Y, Chen, J Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One, 6(9), e24426, 2011.
- Brantley-Sieders, DM, Dunaway, CM, Rao, M, Short, S, Hwang, Y, Gao, Y, Li, D, Jiang, A, Shyr, Y, Wu, DJ, Chen, J Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res, 2010.
- Dunaway, CM, Hwang, Y, Lindsley, CW, Cook, RS, Wu, JY, Boothby, M, Chen, J, Brantley-Sieders, DM Cooperative Signaling Between Slit2 and Ephrin-A1 Regulates a Balance Between Angiogenesis and Angiostasis. Mol Cell Biol, 2010.
- Zhuang, G, Brantley-Sieders, DM, Vaught, D, Yu, J, Xie, L, Wells, S, Jackson, D, Muraoka-Cook, R, Arteaga, C, Chen, J Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res, 70(1), 299-308, 2010.
- Frieden, LA, Townsend, TA, Vaught, DB, Delaughter, DM, Hwang, Y, Barnett, JV, Chen, J Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev Dyn, 239(12), 3226-34, 2010.
- Min, Y, Ren, X, Vaught, DB, Chen, J, Donnelly, E, Lynch, CC, Lin, PC Tie2 signaling regulates osteoclastogenesis and osteolytic bone invasion of breast cancer. Cancer Res, 70(7), 2819-28, 2010.
- 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, 7(5), 615-23, 2009.
- Bogan, C, Chen, J, O''Sullivan, MG, Cormier, RT Loss of EphA2 receptor tyrosine kinase reduces ApcMin/+ tumorigenesis. Int J Cancer, 124(6), 1366-71, 2009.
- Vaught, D, Chen, J, Brantley-Sieders, DM Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Mol Biol Cell, 20(10), 2572-81, 2009.
- Chen, J, Zhuang, G, Frieden, L, Debinski, W Eph receptors and Ephrins in cancer: common themes and controversies. Cancer Res, 68(24), 10031-3, 2008.
- Vaught, D, Brantley-Sieders, DM, Chen, J Eph receptors in breast cancer: roles in tumor promotion and tumor suppression. Breast Cancer Res, 10(6), 217, 2008.
- 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.
- 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, 121(Pt 3), 358-68, 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, 118(1), 64-78, 2008.
- 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, 282(4), 2683-94, 2007.
- 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, 66(21), 10315-24, 2006.
- 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, 26(13), 4830-42, 2006.
- 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.
- Ireton, RC, Chen, J EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets, 5(3), 149-57, 2005.
- 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, 19(13), 1884-6, 2005.
- Brantley-Sieders, Dana M, Chen, Jin Eph receptor tyrosine kinases in angiogenesis: from development to disease. Angiogenesis, 7(1), 17-28, 2004.
- Brantley-Sieders, D, Parker, M, Chen, J Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des, 10(27), 3431-42, 2004.
- 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, 117(Pt 10), 2037-49, 2004.
- 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, 109(12), 1551-9, 2002.
- 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, 21(46), 7011-26, 2002.
- Cheng, Nikki, Brantley, Dana M, Chen, Jin The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev, 13(1), 75-85, 2002.
- 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, 276(17), 13771-7, 2001.
- 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, 273(38), 24670-5, 1998.
- 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, 12(5), 979-88, 1996.