Overview
My laboratory studies two major areas in the field of human papillomavirus (HPV) infection and associated carcinogenesis:
- Specific functions of the HPV oncogenes in the initiation and maintenance of cellular immortality
- Molecular mechanisms of cellular senescence in the context of HPV carcinogenesis
HPV infection and cervical cancer
Human papillomaviruses (HPVs) are a group of small DNA viruses that induce a variety of epithelial lesions in humans ranging from cutaneous and genital warts to invasive cancer. Genital HPVs are the most common sexually transmitted pathogen in the United States and are classified as low-risk and high-risk HPVs based on the clinical lesions in which they are detected and the likelihood of such lesions to progress to malignancy. Cancer of the uterine cervix is the predominant HPV associated cancer, representing the second most common cancer in women worldwide and causing 15% of female cancer mortality. Over 99% of human cervical cancers harbor viral DNA of a high risk HPV and express the viral oncoproteins E6 and E7. Sustained E6/E7 expression is required for both initiation and maintenance of HPV positive carcinogenesis, thus making these proteins excellent therapeutic drug targets. Specific repression of the viral oncogenes in cervical cancer cells results in a form of genetic cell death, cellular senescence. The development of molecular tools for E6/E7 repression in cervical cancer cells and an understanding of senescence as a consequence thereof constitute major research efforts in my laboratory.
Cellular senescence
Members of the Wells Lab are (front, l-r) Susanne Wells, PhD and Trisha Wise-Draper; (back, l-r) Beth Jones, Kristen Habash, and Kristy Schmidlin
Cells can adopt a number of general fates such as proliferation, differentiation, apoptosis and senescence. The terms cellular or replicative senescence define the finite replicative capacity of most somatic cells in culture. Senescence results in the complete and irreversible cessation of cellular division. Several experimental conditions can induce cellular senescence in vitro. Senescence by replicative exhaustion results from telomere attrition with each replicative cycle. Aside from replicative exhaustion, various forms of stress such as DNA damage or oncogene expression can trigger senescence. Cultured cell senescence limits our ability to expand and manipulate somatic cells for replacement therapies ex vivo. Approaches to inhibit senescence pathways (without supporting cellular transformation) may therefore be desirable in clinical applications such as replacement therapies. In limiting the number of times that a given cell can divide in response to intrinsic or extrinsic signals, cellular senescence is thought to represent a natural barrier to cancer development in vivo. This notion is further emphasized by the fact that tumor suppressors such as p53 or pRB, which are frequently inactivated in human cancers in vivo, play important roles during cellular senescence in vitro. Findings from a number of laboratories strongly support an antagonistic relationship between cellular senescence and carcinogenesis in vivo and positively correlate intact senescence pathways with tumor regression following chemotherapy. In addition, senescence has been suggested to underlie aspects of the organismal aging process. Interesting in this regard is the fact that molecules involved in senescence such as telomerase, p53 and BRCA1 can cause aging phenotypes when deleted or mutated in mice. Understanding the regulatory and executive senescence machinery may therefore be of great value for the development of novel approaches to the treatment of carcinogenesis and the loss of functional and proliferative hom.
The details of senescence induction and execution as well as its significance in vivo are poorly understood. We have used microarray analyses and have identified a number of molecular markers and mediators of senescence in cervical cancer cells. We currently focus on the roles of specific genes during senescence and carcinogenesis in the hopes of identifying critical players in the transition from a normal to a malignant cellular phenotype. Our functional studies in the laboratory are interfaced with an assessment of the regulation of individual molecules in benign and malignant human cervical lesions. In applying the basic relationship between senescence and carcinogenesis to clinical studies, we hope to arrive at a better understanding of HPV associated carcinogenesis and to develop new markers and drug targets for improved diagnosis and treatment.
Publications
Wise-Draper TM, Allen HV, Thobe MN, Jones EE, Habash KB, Munger K, Wells SI. The Human DEK Proto-Oncogene Is a Senescence Inhibitor and an Upregulated Target of High-Risk Human Papillomavirus E7. J Virol. 2005 Nov;79(22):14309-17.
Williams, S. S., Aronow, B. J., and Wells, S. I. 2004. Finding the points of no return: gene program signatures for E2-mediated cervical cancer cells. Cancer Drug Discovery and Development. R. A. Shimkets and W. J. LaRochelle (ed.), The Humana Press, Inc. In press.
Wells, S. I., Aronow, B. J., Wise, T. M., Williams, S. S., Couget, J. A., and Howley, P. M. 2003. Transcriptome Signature of Irreversible Senescence in HPV Positive Cervical Cancer Cells. Proc. Natl. Acad. Sci. USA. 100; 7093-7098.
Erturk, E., Ostapchuk, P., Wells, S. I., Zhu, Q., Nepveu, A., Dudley, J. P. and Hearing, P. 2003. Role of CCAAT-displacement protein, CDP, in Adenovirus 5 DNA packaging. J. Virol. 77; 6255-6264.
Wells, S. I., Francis, D. A., Karpova, A. Y., Dowhanick, J.J., Benson, J. D. and Howley, P. M. 2000. Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21CIP-dependent pathways. EMBO J. 19; 5762-5771.
Francis, D. A., Schmid (Wells), S. I., and Howley, P. M. 2000. Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells. J. Virol. 74; 2679-2686.
