Semester

Fall

Date of Graduation

2010

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Robert Wysolmerski.

Abstract

Cancer cell invasion and motility is mediated through actin-rich protrusions that facilitate migration through extracellular matrix and degradation of tissue barriers. Src tyrosine kinase is an essential catalyst of motile actin networks and is a potent mediator of the metastatic program. The Src substrate cortactin is a critical scaffold that links kinase signaling to cytoskeletal dynamics. Both Src and cortactin are overexpressed in several human cancers and their expression is associated with poor prognosis. These proteins are not associated with the initiation of tumorigenesis, but are thought to play a vital role in the metastatic process. The overall aim of my work is to determine the molecular mechanisms by which Src and cortactin promote the invasive cancer phenotype. Further understanding of these processes provided by the following studies, could provide clinical benefits for cancer patients with advanced disease. Study one demonstrates treatment with the Src-targeted small molecule inhibitor saracatinib impairs tumor cell invasion in vitro and lymph node metastasis in vivo. Further, we identify that Src inhibition decreased invadopodia formation and MMP expression in HNSCC cell lines. Study two identifies regulated WT Src activity as essential for governing invadopodia maturation in HNSCC cells and Src transformed fibroblasts. In addition, we establish cortactin phosphorylation downstream of Src as central to this process. In study three we examine the role of the EGFR/MEK pathway upstream of Src and cortactin in regulating cell migration and lamellipodia dynamics. Lastly, study four outlines an attempt to create a transgenic model of HNSCC tumor cell invasion in which cortactin is overexpressed in the oral cavity of tumorigenic mice.

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