EphA2 receptor is a member of the recently cloned Eph family receptor tyrosine kinases (RTKs) that overexpressed in a variety of malignant tumors. The level of EphA2 receptor expression consistently correlates with the degree of malignancy. Overexpression of EphA2 in non-transformed breast epithelial line has led to tumor formation in nude mice. However, the mechanism by which EphA2 overexpression in tumor malignancy remains unclear. Our preliminary data show that overexpression of EphA2 in non-transformed breast epithelial cells MCF10A disrupts their ability to form acini-like spheroids in a three-dimentional culture. In addition, E-cadherin expression is mis-localized in MCF10A cells overexpressing EphA2 receptor. These data suggest high levels of EphA2 may promote malignant behavior through destabilization of cell-cell adhesion. Conversely, blocking EphA2 receptor activation in malignant tumor cells inhibits RhoA GTPase activation, cell migration, and tumor growth in vivo, indicating that EphA2 receptor signaling is required for tumor malignancy. Based on these data, we hypothesize that EphA2 overexpression (1) disrupts cell-cell adhesion through modifying junctional complexes, (2) promotes cell motility by modulation of Vav3-mediated RhoA GTPase activity, and (3) enhances tumor invasion and metastasis in vivo. To test these hypotheses, we specifically propose to:(1) identify mechanisms by which EphA2 overexpression disrupts cell-cell adhesion; (2) investigate whether increased cell motility in EphA2 overexpressing cells is mediated by Vav3- dependent activation of RhoA GTPase; and (3) determine if EphA2 overexpression is necessary and sufficient to promote tumor formation and metastasis in multi-stage transgenic tumor models. The success of this project will not only provide molecular basis of EphA2-induced cell invasion and metastasis, but also provide in vivo pre-clinical data on the effect of EphA2-deficiency or EphA2 overexpression on tumor progression and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114301-02
Application #
7050213
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2005-04-06
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$294,592
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Edwards, Deanna N; Ngwa, Verra M; Wang, Shan et al. (2017) The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ. Sci Signal 10:
Shiuan, Eileen; Chen, Jin (2016) Eph Receptor Tyrosine Kinases in Tumor Immunity. Cancer Res 76:6452-6457
Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18
Rao, Meghana; Song, Wenqiang; Jiang, Aixiang et al. (2012) VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PLoS One 7:e46281
Chen, Jin (2012) Regulation of tumor initiation and metastatic progression by Eph receptor tyrosine kinases. Adv Cancer Res 114:1-20
Zhuang, Guanglei; Song, Wenqiang; Amato, Katherine et al. (2012) Effects of cancer-associated EPHA3 mutations on lung cancer. J Natl Cancer Inst 104:1182-97
Funk, Steven Daniel; Yurdagul Jr, Arif; Albert, Patrick et al. (2012) EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. Arterioscler Thromb Vasc Biol 32:686-95
Brantley-Sieders, Dana M; Dunaway, Charlene M; Rao, Meghana et al. (2011) Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res 71:976-87
Dunaway, Charlene M; Hwang, Yoonha; Lindsley, Craig W et al. (2011) Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis. Mol Cell Biol 31:404-16

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