608-262-8533 (office); 608-262-6407 (lab)
6459 WI Institute Medical Research
BS, 1979, Biochemistry, University of Massachusetts, Amherst
PhD, 1985, University of Wisconsin-Madison
Postdoctoral Research, Laboratory of Peter Howley, National Cancer Institute
Howard M. Temin Professor and Chair of Oncology
Director of the McArdle Laboratory for Cancer Research
Virology Program Leader, UW Carbone Cancer Center
Our lab’s research is focused on understanding the role of human papillomavirus (HPV) in cancer. HPVs cause 5% of all human cancers. These include cervical cancer, other anogenital cancers and a growing proportion of head and neck cancers. Through the use of genetically engineered mice (GEM) we have developed models for HPV-associated cervical, anal and head/neck carcinogenesis, defined the individual roles of viral oncogenes in carcinogenesis in these organs, identified the mechanisms of action by which these oncogenes contribute to carcinogenesis, defined their temporal role in carcinogenesis, and defined the roles of estrogen and its receptor in cervical carcinogenesis and the utility of estrogen receptor antagonists in treating and preventing cervical cancer. Major current directions in the lab that make continued use of the GEM models include understanding the interplay between viral oncogenes and cellular signaling and DNA damage response pathways in causing cancer, and the influences of viral genes on epigenetic regulation and epithelial stem cell biology.
In recent years we have complemented our use of GEM models with the development patient derived xenografts (PDX) models in which human cancers are directly grafted and passaged in immune-deficient mice. PDX models provide us the ability to test new therapeutic approaches for treating human cancers that we have identified through our studies using the GEM models. For example, using our GEM model for HPV-associated anal cancer, we identified that the cellular mTOR pathway is activated, and its inhibition by rapamycin suppresses anal cancer growth. We then demonstrated the therapeutic value of rapamycin in treating human anal cancer using the first human anal cancer PDX model. Likewise, working with our clinical colleagues we have now established an array of PDX models for both HPV-positive and HPV-negative human head and neck cancers that will be used alongside our GEM models for these cancers to define novel therapeutic approaches for treating these cancers.
The papillomaviral life cycle is intricately tied to the differentiation of the host epithelium it infects. Using artificial skin cultures wherein we can recapitulate all the stages of the viral life cycle in differentiating epithelium, we continue our efforts to dissect the role of viral genes and cellular pathways in the viral life cycle. Recently, we established a mouse papillomavirus infection model in laboratory mice. This new model will allow us to use the power of mouse genetics to better understand virus-host interactions involved in infection and possibly also virally-induced cancers.
Member, National Institutes of Health Virology A Study Section, 2013-2019