Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Elena N Pugacheva

Committee Co-Chair

John M Ruppert

Committee Member

Michael D Schaller

Committee Member

Maxim Sokolov

Committee Member

Scott A Weed

Abstract

Metastasis from the primary tumor site is the major cause of death in breast cancer, and acquisition of migration capacity is a key element for successful metastasis. Recently, it was found that expression of NEDD9, a focal adhesion associated scaffolding protein, could be used to switch between two types of single cell movement known as mesenchymal and amoeboid. Control of this "switch" can potentially open up new avenues of treatment against cancer metastasis. Simultaneous inhibition of both types of single cell movement may prevent cancer migration, thus decreasing cancer spreading and increasing survival of cancer patients. For example, forcibly pushing the switch toward amoeboid migration in combination with treatment against the kinase ROCK, a key component of amoeboid movement, might prove to be a vital strategy against metastasis. Currently, such strategies are not available in clinical practice. This project seeks to fill this gap in knowledge and provide new migration-based strategies to treat breast cancer metastases by 1) defining the impact of NEDD9 expression on regulation of mesenchymal invasion in breast cancer cells, 2) deciphering the mechanism and characterizing the key downstream effectors of NEDD9-dependent signaling that contribute to breast cancer mesenchymal migration, and 3) determining the anti-metastatic therapeutic benefit of inhibiting both mesenchymal and amoeboid breast cancer cell movement in vitro and in vivo.

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