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Associate Professor of Pediatrics B.S., Biology, University of Konstanz, Germany, 1992 |
Research Interests |
Squamous cell carcinoma (SCC) is the second most common form of skin cancer, with over 250,000 new cases per year estimated in the United States. Infection with the human papillomaviruses (HPVs) and expression of the two viral oncogenes E6 and E7 is one well defined cause. The high-risk HPV types cause anogenital malignancies such as cervical cancer and a substantial proportion of head and neck cancers. FDA approval of the HPV vaccine Gardasil is expected to reduce disease burden in the future, but its high cost, dosing regimen and the lack of protection for individuals that are already infected pose major obstacles to the field. Therapeutic vaccines and effective antivirals are not yet available. The goal of our studies is to advance our understanding of both HPV-related and –unrelated SCC development, and to develop new approaches to the diagnosis and treatment of HPV as a major cause of cancer worldwide. Two major areas of investigation in the laboratory focus on 1) mechanisms by which the HPV oncogenes subvert the host cell machinery to promote abnormal cell growth and cancer, and 2) the role of specific cellular HPV targets in viral replication and cellular transformation. Model systems utilized include primary human and murine cells and tumors, three-dimensional organotypic epithelial rafts and mouse models of cancer. Functions of the human DEK proto-oncogene The human DEK protein is frequently upregulated in aggressive human tumors such as glioblastoma, melanoma, and bladder cancer. A number of DEK functions have been described in vitro and include DNA supercoiling and possible roles in DNA replication, transcription and splicing. We have demonstrated that DEK suppresses senescence, apoptosis and differentiation in different model systems, thus promoting cellular growth and survival. Furthermore, DEK exhibits oncogenic functions in 3D models of cancer. First, DEK overexpression in human keratinocytes caused hyperplasia in organotypic epithelial rafts, with inappropriate cell cycle progression and expansion of the p63- positive stem and progenitor cell compartment. Second, DEK cooperated with known oncogenes for increased squamous cell tumor formation in immunodeficient mice. Third, DEK knockout mice were partially resistant to chemically induced skin tumorigenesis. Our studies are the first to define DEK as a bona fide oncogene, and current projects are focused on defining the underlying mechanisms of DEK function as an oncogene and to interfere with DEK activities for the development of novel cancer therapies. The role of HPV in Fanconi anemia Fanconi anemia (FA) is a rare primarily autosomal recessive genome instability syndrome where patients are at a dramatically elevated risk of squamous cell carcinoma (SCC) of the head and neck and anogenital tract. Tumors appear early in life, and progress with striking aggressiveness. Conventional clastogenic therapies such as radiation and chemotherapy are often toxic because of the patients’ DNA damage response defects. Development of alternative treatments has been severely limited by the lack of availability of human models of FA SCC. The FA Comprehensive Care Center at CCHMC has offered a unique opportunity for translational studies, and resulting patient-derived 3D SCC models will be exploited to facilitate screens for new therapies, and support preclinical trials for new treatments. Our recent data demonstrate that loss of function of the FA pathway in high risk HPV16 positive keratinocytes stimulates viral and cellular replication in vitro, and malignant transformation in vivo. Based on these findings, we hypothesize that FA genes are modifiers of HPV infection. Experiments to determine the clinical and molecular importance of FA-HPV crosstalk are currently ongoing. |
Selected Publications |
Bourgo, R.J., Braden, W.A., Wells, S.I., and Knudsen, E.S. (2009) Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines. Molecular Carcinogenesis 48: 45-55. Wise-Draper, T.M., Morreale, R.J., Morris, T.A., Mintz-Cole, R.A., Hoskins, E.E., Balsitis, S.J., Husseinzadeh, N., Witte, D..P, Wikenheiser-Brokamp, K.A., Lambert, P.F., and Wells, S.I. (2009) DEK proto-oncogene expression interferes with the normal epithelial differentiation program. American Journal of Pathology 174: 71-81. Hoskins, E.E., Morris, T.A., Higginbotham, J.M., Spardy, N., Cha, E., Kelly, P., Williams, D.A., Wikenheiser-Brokamp, K.A., Duensing, S., and Wells, S.I. (2009) Fanconi anemia deficiency stimulates HPV-associated hyperplastic growth in organotypic epithelial raft culture. Oncogene 28, 674-85. Wise-Draper, T.M., Mintz-Cole, R.A., Morris, T.A., Simpson, DS., Wikenheiser-Brokamp, K.A., Currier, M.A., Cripe, T.P., Grosveld, G.C., and Wells, S.I. (2009) Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo. Cancer Research 69: 1792-1799 Morreale, R.J., Kahn, J.A., Butsch Kovacic, M., Hegde, R.S., Aronow, B.J., and Wells, S.I. (2009) Insights from the transcriptional profiling of human papillomavirus infection and associated carcinogenesis. Molecular Biology of DNA Tumor Virus Gene Products. K. Yoshida (ed). In press: Research Signpost Company. Hoskins, E.E., Gunawardena, R.W., Habash, B., Wise-Draper, T.M., Jansen, M., Knudsen, E., and Wells, S.I. (2008) Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene 27: 4798-4808. Wise-Draper, T.M., and Wells, S.I. (2008) Papillomavirus E6 and E7 proteins and their cellular targets. Frontiers in Bioscience 13: 1003-1017. Spardy, N., Duensing, A., Hoskins, E.E., Wells, S.I., and Duensing, S. (2008) HPV-16 E7 reveals a link between DNA replication stress, FANCD2 and alternative lengthening of telomeres (ALT)-associated PML bodies (APBs). Cancer Research 68: 9954-9963. Jones, E.E., and Wells, S.I. (2006) Cervical cancer and human papillomaviruses: inactivation of retinoblastoma and other tumor suppressor pathways. Current Molecular Medicine 6: 795-808. |
