Degree Type

Dissertation

Date of Award

2014

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

Major

Molecular, Cellular, and Developmental Biology

First Advisor

Ian C. Schneider

Abstract

Currently there are no reliable treatment options for cancer metastasis. The complex cascade of events leading to metastasis reveals a multitude of therapeutic targets, but few of these targets are extensively involved in as many steps as the matrix metalloproteinases (MMPs). The MMP family is the major extracellular matrix (ECM) remodeling enzymes utilized by normal and cancerous cell alike. A therapeutic technique aimed at MMPs has been the subject of much research, but remains elusive due to two major concerns: 1) MMPs are post-translationally activated, usually by other MMPs, resulting in convoluted catalytic networks where activity does not equate expression, and 2) lack of knowledge of both the specific and redundant roles of MMPs in particular microenvironments. Here I address both these concerns by using specific MMP activity probes and inhibitors to study how MMP activity is regulated by a variety of microenvironmental conditions including modulating both the ECM and the signaling factors available to the cells. With this study I have been able to demonstrate novel regulation of MMP activity by ECM stiffness and cellular contractility in pancreatic cancer cells. This response is mediated through a specific MMP, membrane-tethered one MMP (MT1-MMP), which activates secreted MMPs in response to mechanical stimulation. Finally I have shown that MMP activities are differentially modulated by growth factor stimulation and that whole cell MMP activity does not always correlate with localized ECM degradation. These findings bring cancer metastasis research another step closer to being able to effectively target MMPs for therapy.

Copyright Owner

Amanda Michelle Haage

Language

en

File Format

application/pdf

File Size

144 pages

Included in

Cell Biology Commons

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