Deborah Lebman , Ph.D.
Professor

Phone: (804) 828-6783, (804) 828-0448
Dept. Fax: (804) 828-9946
e-mail: dalebman@vcu.edu

Address:
Department of Microbiology & Immunology
Virginia Commonwealth University
Massey Cancer Center Goodwin Research Laboratory Room 290
P.O. Box 980678                                                                                         401 College Street
Richmond, VA 23298-0678

Professional Experience

• B.A. 1974, Dickinson College 
• Ph.D. 1987, University of Pennsylvania 
• Postdoctoral, 1987-1989, DNAX Research Institute of Cellular and Molecular Biology

Research Interests:

Esophageal cancer is one of the deadliest cancers with an overall survival rate of 10-20%.  This statistic is even more concerning when combined with the facts that the incidence of this cancer is increasing and the age of detection is decreasing.  Although recent years have seen improvement in therapeutic approaches, the prognosis remains dismal.  There is a general consensus that a better understanding of the biology of the disease is required for an improvement in outcome.

The cytokine, TGF-beta, plays a role in the development of a wide array of cancers, and several inhibitors of its signaling pathway are currently in clinical trials.  However, targeting the TGF-beta pathway therapeutically is problematic since it can act to both suppress the development of tumors and promote the development of a more aggressive phenotype.  Thus, dissecting the different signaling pathways activated by TGF-beta and understanding the role of each pathway in tumor suppression and tumor promotion is of paramount importance for development of specific and effective therapeutic modalities.  With this in mind, our program focuses on two aspects of TGF-beta signaling and how they relate to the development of esophageal cancer.

SnoN and Attenuation of TGF-beta Signaling

TGF-beta plays a dual role in the development of epithelial cancers acting as both a tumor suppressor and a tumor promoter.  This dichotomy is a reflection of its multiple effects on epithelial growth and differentiation.   It inhibits carcinogenesis by inducing reversible growth arrest in G₁, but it promotes carcinogenesis by stimulating pro-metastatic processes such as migration, invasion and epithelial mesenchymal transition.    During the oncogenic process, epithelial cancers commonly become resistant to TGF-beta induced growth arrest.    In esophageal cancers, resistance to TGF-beta induced growth arrest occurs despite the presence of a functional TGF-beta signaling pathway.  Or in others, TGF-beta can induce signal transduction in the cancer cells, but it cannot induce growth arrest.  Studies from our laboratory demonstrated that this occurs as a result of de-regulation of the SnoN oncoprotein.  TGFb initiates signal transduction by promoting the formation of a heteromer consisting of TGFb receptors I and II.  TbRII activates TbRI resulting in the phosphorylation of the receptor activated Smads, i.e., Smad2 and Smad3 in the case of TGFb1.  The phosphorylated receptor Smad interacts with Smad4 and enters the nucleus and acts in concert with a wide array of transcription factors to induce the TGF-beta gene response.  SnoN binds to Smads and prevents them from acting to regulate transcription.  In normal cells, Smad3 binds to SnoN and directs it to the anaphase promoting complex ultimately leading to degradation.  However, in esophageal cancer cells that are resistant to TGF-beta induced growth arrest, SnoN is not degraded in response to TGF-beta treatment.  Studies in our laboratory are focusing on the molecular and cellular consequences of the de-regulation of SnoN expression as well as the mechanism by which SnoN selectively abrogates Smad-dependent gene responses.

TGF-beta and S1P Pathway Crosstalk

In addition to activation of the canonical Smad-dependent pathway, TGF-beta activates several non-Smad signaling pathways including p38 MAPK, ERK1/2, PI-3K/Akt and JNK.   Although growth arrest relies exclusively on Smad-dependent signaling, the induction of pro-tumorigenic processes such as migration and invasion also requires activation of these non-Smad signaling pathways.  The bioactive lipid mediator sphinogosine 1- phosphate (S1P) and TGF-beta have overlapping biologic effects.  The signaling pathways activated by S1P and TGF-beta also overlap.  In fact, recent studies from our lab demonstrated that crosstalk between these pathways is critical to the ability of TGF-beta to both activate ERK1/2 and induce migration and invasion.  Current studies are focusing on dissecting this pathway crosstalk.

Selected Publications:

Edmiston, J.S. and Lebman, D.A. A Transforming growth factor regulable RNA-binding protein interacts specifically with germline immunoglobulin transcripts. Int. Immunol . 9:427-433. 1997

Coyle, J.H., Borinstein, S.C., Woodward, E.O., and Lebman, D.A. Predominant usage of the proximal poly (A) site in mRNAs is not intrinsic to the 3' termini. Int. Immunol . 10:669-678. 1998.

Lebman, D.A and Edmiston, J.S. The role of transforming growth factor in growth, maturation and differentiation of b cells. Microbes and Ifection . 1:1297-1304. 1999.

Lebman, D.A. and Coyle, J.H. Developmental regulation of immunoglobulin mRNA processing: establishing a paradigm. Immunologic Res. 20:43-53. 1999.

Coyle, J.H. and Lebman, D.A. Correct immunoglobulin mRNA processing depends on specific sequence in the C3-M intron. J. Immunol. 164:3659-3665. 2000.

Guilliano, MJ, Foxx-Orenstein, AE, and Lebman, DA.  The microenvironment of human Peyer’s patches inhibits the increase in CD38 expression associated with the germinal center reaction. J. Immunol.  166:2179-2185. 2001.

Lebman, DA, Edmiston, JA, Chung, TD, and Snyder, SR.  Heterogeneity in the transforming growth factor b response of esophageal cancer cells.  Int. J. Onc.  20:1241-1246. 2002.

Kim,AH, Lebman,DA, Dietz,CM, Snyder, SR, Eley, KW, Chung,TD. Transforming growth factor-b is an endogenous radiosresistance factor in the esophageal adenocarcinoma cell line OE-33. Int. J. Onc . 23: 1593-1599. 2003.

Edmiston, JS, Yeudall, WA, Chung, TD, Lebman, DA. Inability of TGFb to cause SnoN degradation leads to resistance to TGFb induced growth arrest in esophageal cancer cells. Cancer Research 65:4782-4788. 2005.

Lebman, DA, Spiegel, S.  Cross-talk at the cross-roads of sphingosine-1-phosphate, growth factors and cytokines signaling. J. Lipid Res.  In Press  2008.

Miller, AV, Alvarez, SE, Spiegel, S, Lebman, DA.  Sphingosine Kinases and Sphingosine-1-Phosphate are Critical for TGFbeta-Induced ERK1/2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells.  Mol. Cell Biol.  In Press 2008.

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Date Last Modified: 09/03/2009
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