Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Biology

Collaborative Specialization

Developmental Biology

Supervisor

Damjanovski, Sashko

Abstract

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a multifunctional protease implicated in cancer aggressiveness for its ability to promote proliferation, migration, and invasion, particularly at low expression levels. Due to its multidomain structure and cell signalling abilities, MT1-MMP may act as a key regulatory node enhancing ATP production, which may confer further advantages in cell proliferation and motility. Low levels of MT1-MMP that enhance cell growth/movement were examined with respect to cell metabolism. Cells expressing different levels or forms of MT1-MMP were cultured in media containing different metabolites to assess viability, proliferation, and metabolic gene transcript levels. While cells with a cytoplasmic domain deletion in MT1-MMP demonstrated more transcript level changes than cells that differed in MT1-MMP levels, there were no metabolically relevant differences in metabolic gene transcript levels, suggesting MT1-MMP does not modulate key metabolic pathways to confer proliferative advantages.

Summary for Lay Audience

The extracellular matrix (ECM) is a dynamic network of interconnected proteins that provides structural support to cells. As cells move from one location to another within an organism, the ECM must be remodeled to provide space for cells to move through. Cell movement is essential for processes such as development and immune function but is also a key component of various diseases such as cancer. Therefore, ECM remodeling must be tightly controlled as dysregulation can lead to various disease states. While there are many proteins capable of remodeling the ECM, matrix metalloproteinases (MMPs) are arguably some of the most important. In my research, I focused on membrane-type 1 matrix metalloproteinase (MT1-MMP) which is located on the cell surface with parts of this protein extending both outside and inside the cell. Due to this, MT1-MMP functions beyond ECM remodeling and is also capable of communicating with the cell through various signalling pathways. MT1-MMP is commonly abundant in cancer cells which characteristically rely on a modified cellular metabolism (termed the Warburg Effect) to create ATP which further enhances cell proliferation and movement. Therefore, the purpose of my research was to investigate if MT1-MMP played a role in altering cell metabolism to resemble the Warburg Effect by growing cells in different energy sources which included glucose, lactate, pyruvate, or no-sugar. Here, while optimal low MT1-MMP expression levels enhanced proliferation in glucose, MT1-MMP did not affect proliferation in other sugars. Further, MT1-MMP did not affect the expression of several genes involved in the Warburg Effect suggesting MT1-MMP does not modulate cancer cell metabolism at this level of regulation. Expanding our knowledge on the various roles of MT1-MMP is critical to understanding how this protein functions to increase cancer severity and progression.

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