Patrick E. Nyman, PhD

Position title: Lambert Laboratory

PhD in Cancer Biology Awarded Fall 2017

Dissertation Title. Cooperation between HPV and cellular factors in head and neck squamous cell carcinoma.

Dissertation Summary. Human Papillomavirus (HPV) is responsible for a growing subset of Head and Neck Squamous Cell Carcinomas (HNSCC), one of the most common cancers worldwide. In this dissertation, I have examined various cellular factors and their interplay with HPV in head and neck tumorigenesis. In Chapter 3, I examined the effect of loss of the protein and histone deacetylase Sirt1 on E7-mediated tumorigenesis Although previous reports have found that Sirt1 both promotes the HPV viral life cycle and aids in the survival of cancer cell lines, I found that Sirt1 did not contribute to E7-mediated head and neck tumorigenesis. Furthermore, my study provided some evidence to suggest that Sirt1 could be tumor suppressive in HNSCC. In Chapters 4 and 5, I studied the effect of loss of the canonical Notch signaling pathway on HPV-positive and HPV-negative head and neck tumorigenesis, respectively. Receptors of the Notch signaling pathway were recently found to be frequently mutated in both HPV-positive and HPV-negative human HNSCC. In HPV-positive HNSCC, I found that loss of canonical Notch signaling resulted in both increased tumorigenesis and increased tumor severity in conjunction with the HPV oncoproteins E6 and E7 in mice. In the HPV-negative study, I also found that loss of canonical Notch signaling resulted in increased tumorigenesis in conjunction with a gain-of-function p53 mutation in mice. However, it had less of an effect on disease severity compared to what I observed in the HPV-positive study. This mirrored the propensity for HPV-positive HNSCC to present with higher grade of disease than HPV-negative HNSCC and identified differential effects of mutations in the Notch signaling pathway in an HPV-positive or negative context as one potential explanation for the difference. Additionally, I identified increased beta-catenin, which has been previously shown to interact with the Notch signaling pathway, as a potentially relevant consequence of loss of canonical Notch signaling in increasing the incidence of head and neck tumorigenesis.

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