Semester

Spring

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Laura Gibson

Committee Co-Chair

Jun Liu

Committee Member

Linda Vona-Davis

Committee Member

Robert Wysolmerski

Abstract

Nearly 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) are annually diagnosed in the United States. The current standard of care for HNSCC patients consists of chemoradiation often combined with targeted therapeutic agents. However, the five-year survival rate for patients that relapse is < 50%. Patients with recurrent or metastatic disease have a very poor prognosis and typical survive < 12 months due to therapeutic resistance and loco-regional invasive spread. HNSCC invasion is mediated in part by lamellipodia and invadopodia, two actin-based structures responsible for facilitating invasive movement. Key signaling pathways that govern lamellipodia and invadopodia production are hyperactivated or overexpressed in HNSCC, including EGFR, Src, Erk 1/2, and cortactin. The overall goal of this dissertation is to determine how these signaling components regulate lamellipodia and invadopodia production and function in HNSCC. Three studies were completed that address these issues. Study One reveals an anti-invasive function for Abl in invadopodia regulation in HNSCC, results that are contrary to the pro-invasive influence Abl has in breast and other cancer types. Study Two establishes a fundamental role for Src has in HNSCC invasion and metastasis through the use of the dual Src/Abl inhibitor saracatinib. In Study Three we determine the expression and activation levels of Erk 1/2 in HNSCC patient samples and the role of Erk 1/2 cortactin phosphorylation in HNSCC adhesion, migration and lamellipodia persistence. Collectively these studies shed new light into the fundamental mechanisms utilized during various steps in HNSCC invasion, providing the potential for refinement and development of new avenues for therapeutic intervention.

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