ASSISTANT PROFESSOR, BIOCHEMISTRY AND MOLECULAR BIOLOGY
Phone: 402-559-7072 (Office)
Ph.D., University of Alberta, Canada, 2005
Research Opportunities in my laboratory:
Graduate students considered on an individual basis
Medical students, summer research
My primary research interest is to understand the role of oxidative tumor microenvironment in regulating the reciprocal tumor-stroma interactions.
“No man is an island, entire of itself; every man is a piece of the continent, a part of the main.” John Donne (1573-1631)
We now realize that the progression from normal to benign, benign to malignant, malignant to metastatic, as well as therapeutic resistance is driven not just by what is happening inside the tumor cell itself but by reciprocal communication between the tumor cells and their stroma microenvironment. Therefore, targeting the cellular and molecular components involved in events occurring in the tumor microenvironment could be a more effective strategy for cancer treatment. Stroma fibroblasts are the predominant cell type that dictates the outcome (or fate) of cancer cells and hepatocyte growth factor (HGF) is one of the paracrine factors secreted by tumor-associated fibroblasts that activates c-Met on the surface of cancer epithelial cells. Amplification of the HGF/c-Met pathway is implicated in the acquisition of an aggressive phenotype and metastatic potential of breast cancer and is associated with a difficult-to-treat subtype of the basal-like breast cancers (BLBCs). Deciphering the underlying mechanisms that leads to HGF/c-Met activation is therefore crucial in identifying more effective strategies in improving breast cancer therapies. One such mechanism that activates c-Met in cancer cells is an increase in oxidative stress.
Oxidative stress is induced when there is an imbalance in the production of reactive oxygen species (ROS, e.g. O2•- and H2O2) and their removal by the antioxidant network. Furthermore, expression of the HGF sequestering factor (in the extracellular space), thrombospondin-1 (TSP-1) has been shown to be suppressed by ROS. These reports implicate a role of ROS in supporting the oncogenic HGF/c-Met signaling and the development of cancer. However, the intrinsic factor(s) underlying this oxidative-mediated HGF/c-Met signaling are not known. We have recently found that loss of an extracellular antioxidant enzyme, EcSOD, could be one of the key factors that contributes to this ROS-mediated HGF/c-Met activation in breast cancer cells. EcSOD maintains the extracellular redox homeostasis by scavenging superoxide (O2•-) and preventing the formation of other highly reactive ROS such as hydroxyl radical (•OH) and peroxynitrite (ONOO-). While EcSOD is highly expressed in normal mammary epithelial cells, we observed that its gene expression is silenced in > 80% of breast tumors and its expression level shows an inverse correlation with aggressive phenotypes (Teoh-Fitzgerald et al., Oncogene 2012 in press).
Our long-term objectives are to understand the fundamental mechanisms that promote an oxidative tumor microenvironment that fuels the reciprocal communication between tumor cells and their stroma fibroblasts, elucidate the involvement of redox signaling in HGF/c-Met activation, and to provide a clear biochemical rationale to more effectively target not just the tumor cells, but also their “partners in crime”, the fibroblasts with antioxidant-based therapies. Specifically, we will (1) determine whether activation of NADPH oxidases, often detected in breast cancers, contributes to an oxidative tumor microenvironment and render breast cancer cells more susceptible to HGF-mediated tumorigenesis; (2) elucidate the mechanisms involved in EcSOD-mediated suppression of c-Met signaling; (3) investigate the role of a Ras-GEF, P-Rex1, in the tumor promoting effects of HGF-overexpressing mammary fibroblasts. Since upregulation of the HGF/c-Met pathways have been implicated in therapeutic resistance to her2 and EGFR-targeted therapies, we are also interested in combining the use of a clinically relevant sod mimetic plus c-Met inhibitor and an EGFR inhibitor to overcome cross-talk related resistance in breast cancer.
Teoh-Fitzgerald ML*, Fitzgerald MP, Zhong W, Askeland R, Domann FE*: Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis, and metastasis. Oncogene 2012 (in press).
Du J, Nelson E, Smith BJ, Simons AL, Olney KE, Moser JC, Schrock HE, Wagner BA, Buettner GR, Smith B, Teoh-Fitzgerald ML, Tsao M, and Cullen JJ: Regulation of pancreatic cancer growth by superoxide. Mol Carcinog 2012. http://www.ncbi.nlm.nih.gov/pubmed/22392697
Teoh-Fitzgerald ML, Fitzgerald MP, Jensen TJ, Futscher BW and Domann F: Genetic and epigenetic inactivation of extracellular superoxide dismutase promotes an invasive phenotype in human lung cancer by disrupting ECM homeostasis. Mol Cancer Res: 10:40-51, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22064654
Teoh-Fitzgerald ML, Domann, FE: Superoxide Dismutase and Cancer Therapy. In: Spitz D, Dornfeld, K.J., Gius, D., Krishnan, K (ed) Oxidative Stress in Cancer Biology and Therapy. Humana Press, New York, 2012, pp 59-84.
Fitzgerald MP, Gourronc F, Teoh ML, Provenzano MJ, Case AJ, Martin JA and Domann FE: Human Chondrosarcoma Cells Acquire an Epithelial-Like Gene Expression Pattern via an Epigenetic Switch: Evidence for Mesenchymal-Epithelial Transition during Sarcomagenesis. Sarcoma 2011: 598218, 2011. PMCID: 3087947 http://www.ncbi.nlm.nih.gov/pubmed/21559267
Place TL, Fitzgerald MP, Venkataraman S, Vorrink SU, Case AJ, Teoh ML and Domann FE: Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. PLoS One 6: e14617, 2011. PMCID: 3030558 http://www.ncbi.nlm.nih.gov/pubmed/21297970
Fitzgerald MP, Madsen JM, Coleman MC, Teoh ML, Westphal SG, Spitz DR, Radi R and Domann FE: Transgenic biosynthesis of trypanothione protects Escherichia coli from radiation-induced toxicity. Radiat Res 174: 290-6, 2010. PMCID: 2942016 http://www.ncbi.nlm.nih.gov/pubmed/20726720
Teoh ML, Fitzgerald MP, Oberley LW and Domann FE: Overexpression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion. Cancer Res 69: 6355-63, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19602586
Weydert CJ, Zhang Y, Sun W, Waugh TA, Teoh ML, Andringa KK, Aykin-Burns N, Spitz DR, Smith BJ and Oberley LW: Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. Free Radic Biol Med 44: 856-67, 2008. http://www.ncbi.nlm.nih.gov/pubmed/18155673
Teoh ML, Sun W, Smith BJ, Oberley LW and Cullen JJ: Modulation of reactive oxygen species in pancreatic cancer. Clin Cancer Res 13: 7441-50, 2007. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18094428
Teoh ML, Turner PV and Evans DH: Tumorigenic poxviruses up-regulate intracellular superoxide to inhibit apoptosis and promote cell proliferation. J Virol 79: 5799-811, 2005. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15827194
Teoh ML, Walasek PJ and Evans DH: Leporipoxvirus Cu,Zn-superoxide dismutase (SOD) homologs are catalytically inert decoy proteins that bind copper chaperone for SOD. J Biol Chem 278: 33175-84, 2003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12773543
Cao JX, Teoh ML, Moon M, McFadden G and Evans DH: Leporipoxvirus Cu-Zn superoxide dismutase homologs inhibit cellular superoxide dismutase, but are not essential for virus replication or virulence. Virology 296: 125-35, 2002. (Cao and Teoh share first authorhship) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12036324
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley