ORCID Identifier(s)

0000-0001-8129-3172

Graduation Semester and Year

2018

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Young-Tae Kim

Second Advisor

Justyn Jaworski

Abstract

Standard-of-care regimes for cancer treatment have become more effective and sophisticated over the last decade due to research developments which facilitate specific targeting of treatments to certain cancers, and the ability to provide specialized care to cancer patients. However, cancer treatments overall still fall short of preventing spread of disease from the primary tumor to secondary sites where they settle and form new more aggressive tumors. It is this stage of disease progression which results in the majority of cancer deaths. The long-term goal of this research is to develop a system for the effective high throughput screening of chemotherapeutic drugs (and possibly in combination with radiation therapy) that target migrating cancer cells, for metastatic cancer treatment. In Aim 1 we developed a polydimethylsiloxane (PDMS) microfluidic device equipped with microchannels for the study of proteome expression changes that are likely induced through Epithelial-to-mesenchymal (EMT) transition, a result of migration through confined threedimensional (3D) space. Quantification of protein expression differences between cells that migrated, and cells that grew in a classical two-dimensional (2D) environment revealed a pattern of molecular changes associated with EMT which highly invasive MDA-MB-231 breast cancer cells likely underwent while migrating through the microchannels. While examining these differences between cells in the two different conditions, we were inspired to develop an Engineered Basal Lamina (EBL) for 2D culture of breast and lung cancer cells. Coating of cell culture well plates with the EBL revealed a significant difference in both protein expression and chemotherapeutic response from cells grown on the classic polystyrene coating. We further sought to examine in Aim 3, the induction of dedifferentiation of breast cancer cells upon migration through confined space, and the molecular properties associated with this process that render these cells completely unresponsive to Doxorubicin (DOX), a potent breast cancer drug whose mode of action is DNA intercalation and inhibition of macromolecular biosynthesis. We sought to uncover the genetic and epigenetic activities of the cancer cells upon collection from the microchannels and re-culture in a 2D environment, as well as changes associated with multiple and extended migration events. This would likely uncover possible therapeutic targets for cells which have migrated to secondary sites.

Keywords

Breast cancer, Migration, Metastasis

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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