Degree Type

Dissertation

Date of Award

2013

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

First Advisor

Ian C. Schneider

Abstract

Cell migration plays an important role in cancer metastasis. Traditional diagnostic methods often involve obtaining tissue biopsies and examining the morphology of the cells and the molecular composition of the microenvironment in static microscopy images. A link between dynamic cellular processes and static microenvironmental inputs must be made. This connection is often made qualitatively with a lack of quantitative information. Therefore, the aims of this work are to investigate how subcelluar dynamics of cell migration such as protrusion and adhesion are quantitatively modulated under different environmental inputs such as epidermal growth factor (EGF) and collagen.

There are two major subcellular processes of migration, protrusion and adhesion. Protrusion is a dynamic movement of the cell edge and adhesion is mediated through macromolecular complexes called focal adhesions (FA). EGF concentration is an input that regulates FA and protrusion dynamics, whereas cell speed is an output that integrates information determined by inputs such as EGF. Several FA signatures and protrusion waves are associated with fast migration, but not necessarily with EGF. This suggests that other factors like contractility or extracellular matrix (ECM) might alter protrusion and FA for fast migration. Because fast migrating cells are usually invasive and cause metastasis, I designed a high-throughput method to identify the fast cells for determining what differences in cell properties such as protein expression level lead to the cell-to-cell variability. As mentioned above, contractility and ECM adhesivity are other inputs that affect migration. Although their effects on migration may be similar, upstream responses may vary. For example, both increasing adhesivity and decreasing contractility decreased migration speed, but their impact on protrusion and adhesion were distinct. Adhesivity affects migration not only on uniform substrates, but also under contact guidance. Both increasing adhesivity and the number of lines a cell contacted resulted in decreased directionality with more protrusion waves, which suggest that adhesivity and line spacing drive the effciency of contact guidance through the presence of protrusion waves. In summary, quantification of protrusion and FA properties might provide signatures that relate short timescale dynamics to long timescale migrational properties, making them ideal measurements for cancer diagnosis.

Copyright Owner

Yue Hou

Language

en

File Format

application/pdf

File Size

177 pages

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