- Undergraduate Degree: B.A., Biology, University of Delaware
- Graduate Degree: Ph.D., Biology, University of Virginia
- Fellowship: National Institutes of Health
The major project in my laboratory is focused on elucidating the biological properties of TWEAK, a member of the TNF superfamily of structurally-related proteins, and its sole signaling receptor named Fn14. TWEAK:Fn14 engagement stimulates multiple signal transduction pathways, including the NF-kB pathway, and this can trigger various cellular processes (e.g., growth, differentiation, migration, invasion). The TWEAK/Fn14 axis is thought to be a major physiological mediator of tissue repair after acute injury and sustained axis activity has been implicated in chronic inflammatory diseases and ischemic stroke. In addition, various studies have revealed that Fn14 is highly-expressed in many solid tumor types and that Fn14 signaling may play a role in tumor growth and metastasis. Our present research efforts can be categorized as follows:
- Analysis of TWEAK and Fn14 gene regulation; TWEAK and Fn14 structure/function studies; analysis of Fn14 signaling mechanisms
- Determine the role of the TWEAK/Fn14 axis in cancer biology, with particular focus on brain cancer
- Pre-clinical development of Fn14-targeted therapeutics for cancer patients
Winkles, J.A. (2008). The TWEAK-Fn14 cytokine-receptor axis: Discovery, biology, and therapeutic targeting. Nature Reviews Drug Discovery 7:411-425.
Whitsett, T.G., Cheng, E., Inge, L., Asrani, K., Jameson, N.M., Hostetter, G., Weiss, G.J., Kingsley, C.B., Loftus, J.C., Bremner, R., Tran, N.L. and Winkles, J.A. (2012). Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion. American Journal of Pathology 181:111-120.
Zhou, H., Ekmekcioglu, S., Marks, J.W., Mohamedali, K.A., Asrani, K., Phillips, K.K., Brown, S.A.N., Cheng, E., Weiss, M.B., Hittelman, W.N., Tran, N.L., Yagita, H., Winkles, J.A. and Rosenblum, M.G. (2013). The TWEAK receptor Fn14 is a therapeutic target in melanoma: Immunotoxins targeting Fn14 receptor for malignant melanoma treatment. Journal of Investigative Dermatology 133:1052-1062.
Asrani, K., Keri R.A., Galisteo, R., Brown, S.A.N., Morgan, S.J., Ghosh, A., Tran, N.L. and Winkles, J.A. (2013). The HER2- and heregulin-1 (HRG)-inducible TNFR superfamily member Fn14 promotes HRG-driven breast cancer cell migration, invasion and MMP9 expression. Molecular Cancer Research 11:393-404.
Brown, S.A.N., Cheng, E., Williams, M.S. and Winkles, J.A. (2013). TWEAK-independent Fn14 self-association and NF-kB activation is mediated by the C-terminal region of the Fn14 cytoplasmic domain. PloS ONE 8:e65248.
Zhou, H., Hittelman, W.N., Yagita, H., Cheung, L.H., Martin, S.S., Winkles, J.A. and Rosenblum, M.G. (2013). Antitumor activity of a humanized, bivalent immunotoxin targeting Fn14-positive solid tumors. Cancer Research 73:4439-4450.
Cheng, E., Armstrong, C.L., Galisteo, R. and Winkles, J.A. (2013). TWEAK/Fn14 axis-targeted therapeutics: Moving basic science discoveries to the clinic. Frontiers in Immunology 4:473.
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