Jill Siegfried, PhD
Professor and UPMC Chair, Lung Cancer Research
Department of Pharmacology and Chemical Biology
Email: siegfriedjm@upmc.edu
M.Phil.; Yale University; 1978
Ph.D.; Yale University; 1981
RESEARCH EXPERTISE:
Dr. Siegfried investigates the role of growth factors and hormones in the development and growth of human lung cancer. The laboratory focuses on the effects of these cytokines on activation of cell signaling pathways and control of tumor growth, as well as their role in risk for cancer. Growth factors and their receptors currently under investigation include estrogen and its receptors and hepatocyte growth factor and its receptor, c-Met. Growth factors and hormones are also being investigated as possible therapeutic targets and diagnostic or prognostic indicators for lung cancer. Hepatocyte growth factor has been found to be a strong negative prognostic indicator for non-small cell lung cancer, and expression of the enzyme aromatase that mediates estrogen production has also been linked to poor outcome in women with lung cancer. Circulating growth factor levels may also correlate with active cancer. These studies are directed toward development of new methods to identify undetected lung cancer and new therapeutic strategies through increased knowledge of growth-regulatory processes in lung cancer cells.
Hepatocyte growth factor (HGF) and its receptor c-Met are a ligand-receptor pair that initiates signaling pathways promoting proliferation, survival, angiogenesis, and invasion. HGF is a mainly paracrine growth factor that is secreted by fibroblasts in the lung and acts upon the c-Met receptor expressed by airway epithelial and endothelial cells. In lung cancer, c-Met is often upregulated and the tumor cells induce elevated HGF production by neighboring stroma. Elevated HGF in lung cancer patients with early stage disease has identified a population of patients who are most likely to recur and die from their disease. As shown in the Kaplan-Meier survival curves, HGF levels above the median of 22 units was associated with a higher proportion of deaths from all causes (A), lung-cancer specific deaths (B), and recurrence events (C). This observation among others has led us to focus on therapeutic targeting of HGF and its receptor c-Met for control of lung cancer.
To test therapeutic strategies, Dr. Siegfried has engineered a transgenic mouse that over-expresses the human HGF gene in the airways by placing the HGF gene under the control of the Clara cell secretory protein (CCSP) promoter. The lungs of these mice produce human HGF mRNA and protein and contain 2-3 times as many clara cells per micron of airway length as wild-type mice. While the mice show some abnormalities in airway branching, they have normal airway function and they do not develop lung tumors spontaneously at a rate above that of wild-type animals. However, the HGF transgenic mouse is more susceptible to the development of lung tumors initiated by the tobacco carcinogen NNK. Lung tumors produced by carcinogen treatment in the HGF transgenic animal are more invasive and contain higher numbers of blood vessels than wild-type tumors. These effects can be inhibited by a neutralizing antibody to HGF that is now in development for clinical use.
The Siegfried laboratory was one of the first to demonstrate the functional significance of estrogen receptors in lung tumors. This figure shows immunohistochemical staining of a non-small cell lung tumor for the estrogen receptor ß, which we have found to be expressed to some degree in over 85% of lung tumors. Staining is observed both in the nucleus and cytoplasm, and we have evidence that both nuclear signaling through ERE elements in the promoter regions of estrogen-sensitive genes, as well as non-nuclear signaling through the EGFR and MAPK pathway occur in lung tumor cells.
Dr. Siegfried also has evidence that estrogen is locally produced by the enzyme aromatase within lung tumors, and this suggests an autocrine ligand-receptor exists for estrogen and its receptor in many lung tumors. Clinical trials are currently on-going to test the clinical activity of estrogen antagonists for therapy of lung cancer.
Selected Publications
Ostrow KL, Hoque MO, Loyo M, Brait M, Greenberg A, Siegfried JM, Grandis JR, Gaither Davis A, Bigbee WL, Rom W., Sidransky D. Molecular analysis of plasma DNA for the early detection of lung cancer by quantitative Methylation-specific PCR. Clin Cancer Res 2010 16(13):3463-72. PMCID2899894.
Stabile LP, Rothstein ME, Keohavong P, Lenzner D, Land S, Gaither-Davis A, Kim KJ, Kaminski N, Siegfried JM. Targeting of both the c-Met and EGFR pathways results in additive inhibition of lung tumorigenesis in transgenic mice. Cancers 2010 2, 2153-70 d. PMCID3049550.
Zeng X, Hood, BL, Sun M, Conrads TP, Day RS, Weissfeld JL, Siegfried JM, William L. Bigbee WL. Lung cancer serum biomarker discovery using glycoprotein capture and liquid chromatography mass spectrometry. J Proteome Res 2010 9(12):6440-9. PMCID3184639.
Ostroff, R, Bigbee, WL, Franklin, W, Gold L, Mehan M, Miller Y, Pass HI, Rom W, Siegfried JM, Stewart A, Walker JR, Weissfeld, JL, Williams S, Zichi D, Brody E. Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer. PLos One 2010 5(12):e15003. PMCID2999620.
Siegfried JM. Early changes in pulmonary gene expression following tobacco exposure shed light on the role of estrogen metabolism in lung carcinogenesis. 2010 Cancer Prev Res 3:707-17. PMCID2881174.
Zeng X, Hood BL, Zhao T, Conrads TP, Sun M, Gopalakrishnan V, Grover H, Weissfeld JL, Wilson DO, Siegfried JM, Bigbee WL. Lung Cancer Serum Biomarker Discovery Using Label Free Liquid Chromatography Tandem Mass Spectrometry. 2011. J Thoracic Oncol. 6:725-734. PMCID3104087.
Bigbee WL, Gopalakrishnan V, Weissfeld JL, Wilson DO, Dacic S, Siegfried JM, Lokshin AE. A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals found to be Cancer-Free by CT Screening. 2012 J. Thoracic Oncol. PMCID3388353.
Stabile LP, Dacic S, Land SR, Lenzer D, Dhir R, Aquafondata M, Landreneau RJ, Grandis JR, Siegfried. Combined analysis of estrogen receptor beta-1 and progesterone receptor expression identifies lung cancer patients with poor outcome. 2011 Clin Cancer Res 17:154-64 PCMID3050630.
Dulak, A., Gubish, CT, Stabile, LP, Henry C, and Siegfried JM. HGF-Independent Potentiation of EGFR Action by c-Met. 2011 Oncogene 30(33):3625-35 PMCID3126872.
Keohavong P, Kahkonen B, Kinchington E, Yin J, Jin J, Liu X, Siegfried JM, Di, YP. K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation. 2011 Anticancer Res 31(9):2877-82. PMID 21868532.
Wilson DO, Ryan A, Fuhrman C, Schuchert M, Shapiro S, Siegfried JM, Weissfeld J. Doubling times and CT screen detected lung cancers in the Pittsburgh Lung Screening Study (PLuSS). 2011 Am J. Respir Crit Care Med. PMCID3262038
Buch SC, Diergaarde B, Nukui T, Day RS, Siegfried JM, Romkes M, Weissfeld JL. Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer. 2011 Mol Carcinog PMCID3289753.
Xu H, Stabile LP, Gubish CT, Gooding WE, Grandis JR, Siegfried. Dual blockade of EGFR and c-Met abrogates redundant signaling and proliferation in head and neck carcinoma cells. 2011 Clin Cancer Res.17(13):4425-38. PMCID3138116.
Horne ZD, Jack R, Gray ZT, Siegfried JM, Wilson DO, Yousem SA, Nason KS, Landreneau RJ, Luketich JD, Schuchert MJ. Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in Stage IA non-small cell lung cancer. 2011 J Surj Res PMID21571304.
Siegfried JM, Gubish CT, Rothstein ME, Henry C, Stabile LP. Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer. J Thorac oncol. 2012 PMCID3288546.
Carr SR, Schuchert MJ, Pennathur A, Wilson DO, Siegfried JM, Luketich JD, Landreneau RJ. Impact of tumor size on outcomes after anatomic lung resection for stage 1A non-small cell lung cancer based on the current staging system. J Thorac Cardiovas Surg. 2012 143(2):390-7. PMID22169444.
Tessema M, Yingling CM, Thomas CL, Klinge DM, Bernauer AM, Liu Y, Dacic S, Siegfried JM, Dahlberg SE, Schiller JH, Belinsky SA. SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15. Oncogene 2011 doi: 10.1038/onc.2011.577 PMCID3307938.
Leng S, Stidley CA, Liu Y, Edlund CK, Willink RP, Han Y, Landi MT, Thun M, Picchi MA, Bruse SE, Crowell RE, Van Den Berg D, Caporaso NE, Amos CI, Siegfried JM, Tesfaigzi Y, Gilliland FD, Belinsky SA. Genetic determinants for promoter hypermethylation in the lungs of smokers: A candidate gene-based study. Cancer Res. 2012 PMCID3271143.
