Patrick E. Nyman, PhD

Position title: Lambert Laboratory

Address:
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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