All ETDs from UAB

Advisory Committee Chair

Mary-Kathryn Sewell-Loftin

Advisory Committee Members

Anna G Sorace

Lalita A Shevde-Samant

Document Type

Thesis

Date of Award

2023

Abstract

Mechanical stimulation has been found to be an important regulator of nearly all biological processes, from maintaining normal homeostatic conditions to promoting pathological mechanisms of multiple diseases including cancer. While our knowledge of cancer continues to grow, our current models often lack the biophysical forces that are present in the body which could explain why numerous promising therapeutic agents discovered in research fail to translate into clinical efficacy. This study aims to demonstrate that breast cancer progression is mediated by strains in the tumor microenvironment (TME) in conjunction with trans-membranous glycoprotein receptor, CD44. There are many different sources of strain in the TME such as compression in the tumor core, tension on the periphery, and extracellular matrix (ECM) distortions caused by remodeling and movement of cells. Cancer associated fibroblasts (CAFs) are a common stromal cell type found in the TME of breast cancer which remodel and distort the ECM more than normal fibroblasts found in healthy tissue, which leads to an increase in the amount of strain in the TME. There are many different cellular and non-cellular components in the TME that generate a dynamic and complex environment which is difficult to reproduce in vitro. Hyaluronic acid (HA) is a common ECM component that has been shown to promote breast cancer progression through the glycoprotein, CD44. This study utilizes a highly versatile and advanced microfluidic device which mimics the TME and provides the ability to control for and investigate biomechanical regulation of breast cancer behaviors. A triple negative breast cancer model line, MDA-MB-231 (231), a were loaded into the microfluidic devices in either Fibrin or Fibrin+HA 3D matrices. To study how cell -induced matrix distortions altered 231 migration and proliferation, CAFs or normal breast fibroblasts (NBFs) were added to adjacent regions in the microfluidic model and cultured for 12 days . Through the use of shRNA knockdowns for CD44 in the 231 cells, we were able to test the effect that HA in the TME had on breast cancer metastasis. This study will help to increase our understanding of how mechanical forces affect breast cancer metastasis.

Share

COinS