Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

John M Ruppert

Committee Co-Chair

Erik Bey

Committee Member

Laura Gibson

Committee Member

Fred Minnear

Committee Member

Michael Schaller

Abstract

Breast cancer is a devastating and complicated disease. A large proportion of breast cancer related deaths are due to metastasis. Metastasis is when cancer cells leave the primary tumor, travel through the bloodstream, and proliferate in distant sites. Cell contractility is involved in a number of cellular processes associated with metastasis including matrix organization, tumor cell migration, and endothelial cell barrier function. The main regulator of contractility in nonmuscle cells is nonmuscle myosin II. There are three isoforms of this protein: myosin IIA, IIB, and IIC. The specific roles of the individual isoforms in cancer progression and metastasis have yet to elucidated. This works aims to determine if myosin II isoforms play separate roles in three functions associated with cancer progression: tumor cell organization of a collagen matrix, tumor cell migration, and endothelial cell barrier function. In Study 1, the ability of breast cancer cells lacking myosin II isoforms to organize a collagen matrix was assessed. In addition, the migration potential of these cells in 3D matrices was measured. Myosin II isoforms were found to play distinct roles in cancer cell matrix organization and cell migration. In Study 2, the barrier function of endothelial cells lacking myosin II isoforms was tested. This cell function is involved in metastasis when cancer cells cross the blood vessel wall to enter and exit the bloodstream. Both myosin II isoforms were found to be involved in endothelial cell contractility, and the IIA isoform was found to be necessary for barrier function. Collectively, these studies indicate that myosin II isoforms play distinct and non-redundant roles in cell processes associated with cancer metastasis.

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