Credentials: Cancer Biology Graduate Program
Position title: Lambert Laboratory 2012-Current
M6459 WIMR, II
1111 Highland Ave
Madison, WI 53705
Research Title: The Role of EGFR in HPV-associated Cancers
Research Description: Research in the Kimple Laboratory (September 2013-May 2014): Human papillomavirus (HPV) plays an etiologic role in a growing subset of head and neck cancer (HNC) patients and is likely to become the predominant cause of HNC over the next decade. Patients with HPV-positive (HPV+) HNC show improved outcomes compared to those with HPV-negative (HPV-) HNC. This is consistent with studies that have identified significant molecular and genetic differences between these two cancers. Epidermal growth factor receptor (EGFR) expression appears to be lower in HPV+ than in HPV- HNCs; a finding without a known biological explanation but with important potential clinical relevance given the usage of EGFR inhibitors in HNC therapy. A better understanding of the mechanistic modulation of EGFR signaling by HPV will not only shed light on cancer development and anti-cancer therapy but may also provide insight into the role of EGFR signaling pathways in the viral life cycle. Preliminary data shows expression and activation of EGFR and its downstream signaling pathways in our HPV+ HNC cells and that this expression and activation is decreased in the presence of an EGFR inhibitor correlating with both decreased proliferation and survival in HPV+ HNC cells.
Research in the Lambert Laboratory (May 2014 to present): High-risk HPVs are non-enveloped dsDNA viruses that infect stratified squamous epithelia and cause a majority of cervical cancer, other anogenital cancers, and a subset of head and neck squamous cell carcinomas. HPVs encode three oncogenes: E5, E6, and E7. Multiple studies have implicated the EGFR, a receptor tyrosine kinase aberrantly expressed in multiple epithelial cancers, in transformation by HPV oncogenes. Dr. Alan Rapraeger (UW-Madison) recently discovered that syndecans (Sdc), a family of matrix receptors, contain specialized docking sites in their extracellular domains for integrins and growth factor receptor tyrosine kinases. In squamous carcinomas, overexpression/hyperactivation of EGFR leads to phosphorylation of the α6β4 integrin. This phosphorylation, mediated by complex formation with Sdc1, promotes the proliferation, survival, and invasion of tumor cells. Two methods have been developed to inhibit Sdc-mediated activation of integrins by EGFR. One method is the use of a β4 mutant, β41355T, which specifically interferes with Sdc1 complex formation. The other method is use of the synstatin, SSTNEGFR, a short peptide that mimics the site in the Sdc1 ectodomain responsible for capturing α6β4 integrins in a complex with EGFR. Interestingly, only carcinoma-derived cells are sensitive to synstatin (normal keratinocytes are not sensitive to synstatins), suggesting that the sdc/integrin/EGFR complex is of unique importance to cancers. Alexandra has performed initial studies that indicate that synstatins including the one specific to the EGFR complex, another specific for the IGFR complex and a third specific for the Her2 complex, together can inhibit the growth of HPV16-positive cell lines derived from a precancerous cervical lesion in a woman. This striking result implicates the syndecan/ integrin/growth factor complexes in driving cell proliferation/survival of HPV-infected cells. These initial studies will provide a new direction for addressing the role of EGFR and perhaps other growth factor receptors in HPV-associated cancers.