Ephrin-A1 in Tumor-Endothelial Interaction During Metastasis Tumor metastasis is a primary cause of death in cancer patients. The overall goal of this research program is to develop key new insights into regulation of tumor metastasis through the study of tumor cell-endothelial cell interaction. The specific goal of this project is to investigate the role of membrane-bound ephrin-A1, a prototypic ligand for EphA receptor tyrosine kinases, in two critical steps of tumor metastasis, vessel recruitment and tumor cell intravasation. Based on our preliminary data and reports from other laboratories, we hypothesize that ephrin-A1 promotes tumor metastasis through coordinated induction of angiogenic factors and direct activation of EphA2 receptors on vascular endothelial cells. To test this hypothesis, Specific Aim 1 will investigate how soluble angiogenic factors, VEGF and leptin, and membrane-bound ephrins coordinate recruitment of blood vessels. We will determine whether ephrin-A1 regulates VEGF and leptin separately or if induction of leptin is prerequisite for elevation of VEGF. The role of leptin in cancer will be determined in vivo by using leptin neutralizing antibodies or soluble leptin receptors. The specific role of leptin in tumor angiogenesis will be analyzed in endothelial-specific leptin receptor knock out mice.
Specific Aim 2 will dissect ephrin- A1/EphA2 interaction and signaling in tumor angiogenesis and intravasation. Two novel model systems, the chick embryo metastasis model and the tumor-microenvironment bioreactor, will be used for visualization and quantification of tumor cell intravasation. To study ephrin-A1/EphA2 signaling, an EphA2-null temperature-sensitive immortalized endothelial cell system will be reconstituted with wild-type or mutant EphA2 receptors and tested for binding to interacting proteins, activation of downstream signaling pathways, and the tumor cell-endothelial cell interaction that is required for angiogenesis and intravasation.
Specific Aim 3 will determine the role of ephrin-A1 in tumor metastasis in MMTV-Neu and MMTV-PyMT transgenic breast cancer models, using newly created ephrin-A1 knock out mice. Taken together, the success of this project will not only provide critical insights into the rate-limiting steps of tumor metastasis, but also provide new potential therapeutic targets for treatment of this devastating disease. Project Narrative The goal of this project is to investigate the mechanisms by which cancer cells disseminate into secondary organs in a process called metastasis. Two critical rate-limiting steps in metastasis involve the interaction of tumor cells and blood vessels, in which a novel molecule, termed ephrin-A1, may play a critical role. Experiments were proposed in this application to test ephrin-A1 function in tumor metastasis, and success of this project will not only provide critical insights into the rate-limiting steps of tumor metastasis but also provide new potential therapeutic targets to inhibit this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095004-10
Application #
8277363
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2002-04-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$291,193
Indirect Cost
$101,491
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
Youngblood, Victoria M; Kim, Laura C; Edwards, Deanna N et al. (2016) The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer. Cancer Res 76:1825-36
Kim, L C; Cook, R S; Chen, J (2016) mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene :
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
Shiuan, Eileen; Chen, Jin (2016) Eph Receptor Tyrosine Kinases in Tumor Immunity. Cancer Res :
Youngblood, Victoria; Wang, Shan; Song, Wenqiang et al. (2015) Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium. Mol Cancer Res 13:524-37
Chen, Jin; Song, Wenqiang; Amato, Katherine (2015) Eph receptor tyrosine kinases in cancer stem cells. Cytokine Growth Factor Rev 26:1-6
Wang, Shan; Amato, Katherine R; Song, Wenqiang et al. (2015) Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol 35:1299-313
Amato, Katherine R; Wang, Shan; Hastings, Andrew K et al. (2014) Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest 124:2037-49
Song, Wenqiang; Ma, Yufang; Wang, Jialiang et al. (2014) JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res 74:2444-54
O'Neal, Wesley T; Griffin, William F; Dries-Devlin, Jessica L et al. (2013) Ephrin-Eph signaling as a potential therapeutic target for the treatment of myocardial infarction. Med Hypotheses 80:738-44

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