Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Elena N Pugacheva

Committee Co-Chair

Stephen G Graber

Committee Member

Alexey V Ivanov

Committee Member

William P Petros

Committee Member

John M Ruppert

Abstract

The spread of cancer, known as metastasis, is the major cause of relapse and inability to cure disease. Invasion of cancer cells into neighboring tissue and to distant sites allows cancer cells to evade therapeutic agents, due to the low therapeutic penetration of certain tissues such as the central nervous system, and eliminates the feasibility of resection; which is why the study of pro-metastatic proteins is of great urgency, one such protein is NEDD9. NEDD9 is overexpressed in various tumor types and is correlated with poor prognosis due to a more invasive and metastatic phenotype. NEDD9 serves as a scaffolding protein at the intersection between cell proliferation, through activation of mitotic Aurora A kinase (AURKA), and invasion, through regulation of Src kinase and matrix metalloproteinase 14, MMP14, activity. The overall aim of my work is to determine the role of NEDD9 in tumorigenesis and its implications on AURKA activity in tumor cells. AURKA is up regulated in the majority of human cancers, but not in normal cells making it a promising target for therapeutic interventions. There are several highly specific AURKA small molecule inhibitors in clinical trials to treat cancer. Nevertheless, it was unknown how NEDD9 binding to AURKA affects inhibitor efficacy, AURKA degradation, proliferation, and migration of tumor cells. My current studies have answered some of these critical questions allowing for further improvements of AURKA based therapeutics leading to prolonging patient survival. Study one demonstrates that NEDD9 protects AURKA from degradation and limits the successful application of AURKA inhibitors leading to greater metastasis. Additionally, we established that the AURKA inhibitor MLN8237 (Alisertib), currently in Phase III clinical trials to treat advanced lymphomas, has the ability to eliminate breast cancer metastases. Study two establishes NEDD9 as a necessary scaffolding protein for invasion of breast cancer cells by regulating the activity of a key extracellular matrix (ECM) degrading enzymes such as MMP14 and its inhibitor, TIMP2. Study three illustrates the ability of NEDD9 overexpression to increase MMP dependent mammary gland development and potentially promote tumorigenesis in a transgenic animal model. Furthermore, study three details the development of a conditional NEDD9 transgenic mouse strain that can be utilized for various studies. Finally, study four details the method and feasibility of utilizing patient derived xenograft models for future AURKA inhibitor testing in the treatment and prevention of metastatic breast cancer. Taken together, this thesis illustrates the importance and clinical applications of studying the NEDD9-AURKA signaling hub in treating tumor metastasis.

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