Assistant Professor of Oncology Department of Cancer Genetics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone: (716) 845-1033
Fax: (716) 845-1698
E-mail: Andrei.Bakin@RoswellPark.org
General Research Interest
Signal transduction pathways in cancer progression and metastasis
Current Program
Transforming Growth Factor beta (TGF-β) in control of epithelial-mesenchymal transition and cell migration
TGF-β in tumor invasion and microenvironment
TGF-β in control of metabolic pathways involving glutathione
Laboratory Personnel
Alfiya Safina, PhD
Megan Gervasi, BS (Graduate Student)
Michael Cummings, BS (Graduate Student)
Gina Castellanos, BS (Graduate Student)
Description of Research
The research program explores tumor physiology and tumor microenvironment, two major aspects of tumor biology underlying cancer progression and metastases. Our research is primarily focused on breast cancer, the third most common cause of cancer death in the United States. The progression of cancer is critically dependent on the microenvironment in which a tumor originates. The microenvironment controls the tumor growth and the ability to progress and metastasize. It also impacts the efficiency of cancer treatment and the development of drug resistance. Tumor and host cells secrete and activate various factors that ultimately affect all components of the microenvironment (Figure 1).
Our research is focused on transforming growth factor β1 (TGF-β1), a major cytokine in the tumor microenvironment. TGF-β1 plays a prominent role in cancer as well as in normal development and homeostasis. TGF-β1 is a potent inhibitor of cell growth and can induce apoptosis in responsive cells. In early-stage cancers, TGF-β1 functions as a tumor suppressor, and alterations in the TGF-β1 pathway are implicated in cancer development (Roberts and Wakefield 2003). Paradoxically, advanced tumors secrete abnormally high levels of TGF-β1, and this is associated with tumor invasion and metastases (Roberts and Wakefield 2003). Understanding the molecular mechanism(s) behind the oncogenic TGF-β1 function is a major focus of our research. The goal is to develop better diagnostic tools and cancer treatment.
Figure 1. TGF-β and tumor microenvironment
TGF-β in Epithelial to mesenchymal transition and cell migration
EMT and the reverse process of mesenchymal-epithelial transition (MET) are important in normal embryonic development, wound healing, as well as in tissue fibrosis and cancer. EMT has been linked to the acquisition of the motile phenotype in tumor cells. The EMT process involves the disruption of epithelial cell architecture and remodeling of the cell cytoskeleton.
Early studies explored TGF-β1 signal transduction events contributing to EMT. We have reported that EMT by TGF-β1 requires p38 MAP kinase and Smad transcription factors (TFs), as well as de novo protein synthesis (Bakin, Rinehart et al. 2002; Bakin, Safina et al. 2004; Zheng, Safina et al. 2008). Importantly, we have identified tropomyosin (TPM1) as a critical mediator of actin remodeling by the TGF-β1-Smad pathway (Bakin, Safina et al. 2004). Tropomyosin promotes actin fibers and supports cell-matrix adhesions but restricts cell motility and invasion (Zheng, Safina et al. 2008). In metastatic cells, this TGF-β1 response is lost due to silencing of TPM1 by hypermethylation (Varga, Stourman et al. 2005). As a result, TGF-β1 stimulates motility and invasion in tumor cells. These findings led to a two-step model of the metastatic progression (Figure 2) (Zheng, Safina et al. 2008).
Figure 2. Two-step model of EMT in metastasis. TGF-β induces EMT in normal cells and early-stage tumors leading to tropomyosin-stabilized actin fibers that restrict cell motility. The acquisition of the metastatic phenotype requires the suppression of tropomyosins via epigenetic and/or oncogenic pathways.
TGF-β1 in regulation of tumor invasion and tumor microenvironment
This program investigates the TGF-β regulation of tumor invasion and microenvironment. We have found that tumor TGF-β signaling contributes to tumor angiogenesis and invasion via a mechanism involving matrix metalloproteinase 9 (MMP9) (Safina, Vandette et al. 2007). The follow-up study identified TAK1 as a critical mediator of the TGF-β regulation of MMP9 (Safina, Ren et al. 2008). Therapeutic targeting of TGF-β or MMP9 is complicated due to the tumor suppressor function of TGF-β and multiple complications of MMP9 inhibitors. TAK1 may provide an opportunity for a selective inhibition of pro-oncogenic function of TGF-β. We have filed a provisional application for a patent and initiated collaboration with Dr. Huw Davies, SUNY Buffalo, to develop TAK1 inhibitors. We also explore the role of TAK1 in tumor angiogenesis and tumor-induced bone lesions.
TGF-β1 in regulation of metabolic pathways
Metabolic pathways controlling reactive oxygen species (ROS) and glutathione metabolism play important roles in normal and tumor cells. In collaboration with Dr. Michael Freeman, Vanderbilt University, we have found that TGF-β1 via Smad transcription factors controls expression of over 30 genes involved in key steps of these metabolic pathways (Bakin, Stourman et al. 2005). The current research elucidates the molecular mechanism and the biological significance of these TGF-β responses in cell and animal model systems.
Key Publications
Safina A, Ren MQ, Vandette E, Bakin AV. TAK1 is required for TGFb1-mediated regulation of matrix metalloproteinase-9 and metastasis. Oncogene 2008; 27(9):1198-1207. Safina A, Vandette E, Bakin AV. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 2007; 26(17);2407-2422. Varga AE, Quan L, Stourman NV, Safina A, Li X, Sossey-Alaoui K, Bakin AV. Silencing of the tropomyosin 1 gene by DNA methylation alters tumor suppressor function of TGF beta. Oncogene 2005; 24(32):5043-5052. Bakin AV, Sekhar K.R., Stourman NV, Rinehart C, Yan X, Meredith MJ, Arteaga CL, Freeman ML. Smad Signaling Suppresses Phase II Gene Expression. Free Radic Biol Med 2005; 38(3):375-387. Bakin AV, Rinehart C, Safina A, Daroqui C, Darbary H, Helfman D. A critical role of tropomyosins in TGF-ß regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 2004; 15(10):4682-4694. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFß-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 2002; 115(15);3193-3206. .
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