Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Scott A Weed

Committee Co-Chair

Michael D Schaller

Committee Member

John M Hollander

Committee Member

Karen H Martin

Committee Member

Elena N Pugacheva

Committee Member

Robert B Wysolmerski

Abstract

Metastasis of primary tumor lesions is the leading cause of cancer-related death. In head and neck cancer, a local-regional disease, metastasis is achieved mainly through invasion into surrounding tissue and spreads to cervical lymph nodes. Movement from the initial tumor site requires dynamic reorganization of the actin cytoskeleton, which utilizes the coordinated action of many actin regulatory proteins. However, there is increasing evidence that the tumor microenvironment is also a driver of invasion. This work aims to determine the contributions of proteins which regulate the actin cytoskeleton during head and neck cancer invasion both in vitro and in vivo, and provide details on how the HNSCC tumor microenvironment influences progression. This was accomplished, by the following Studies. In Study one, the actin binding protein coronin 1B is found to be amplified and overexpressed in invasive HNSCC patient samples, and a novel function in the regulation of protrusive membrane structures called invadopodia is described. Study two defines an in vivo role for the actin regulatory protein cortactin, which has been previously associated with more aggressive cancers in vitro and in patients. This work finds that cortactin expression is dispensable for tongue tumor invasion in a transgenic model of oral cancer, implicating the tumor microenvironment as being the major contributor to driving oral cancer invasion. Study three describes a technique for monitoring and biopsying cervical lymph nodes of mice using high frequency ultrasound. By using this technique, alterations in cervical lymph node size and blood flow were discovered in mice given the carcinogen 4-NQO to induce oral carcinogenesis. Collectively, these studies shed light on the importance of choosing comprehensive model systems for studying roles of actin binding proteins in cancer invasion.

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