Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Karen A. Beningo

Abstract

Mechanical forces play an important role in the regulation of cellular behavior and physiological processes including adhesion, migration, proliferation, tissue repair, embryogenesis and development. In addition, a number of diseases including cancer, have been linked to changes in cellular and extracellular mechanical properties. However, whether a correlation exists between the progression of cancer towards metastasis and mechanical factors has not been clearly defined. Additionally, how a cell responds to changes in extracellular mechanical cues as it gains metastatic abilities is poorly understood. To address these questions, we have utilized a panel of murine breast cancer cell lines with progressive metastatic. We have asked how the cells ability to produce mechanical forces changes as the cells progress in metastatic abilities. Furthermore we have asked if metastatic progression changes the cells ability to respond to altered extracellular mechanical cues in two-dimensional in-vitro cultures. Our results indicate that with metastatic progression, the strength of adhesion and traction stress progressively decreases. Furthermore we observe a downward trend in the number of focal adhesions at the leading edge, and subsequent reduction in the activation of integrin beta1 and migration speed. We have also found that this cell panel loses its ability to sense changes in compliance as metastatic abilities increase and that this occurs in a fibronectin dependent manner. We found that the loss in mechanical sensing is associated with a decrease in integrin (alpha3)beta1 activation and FAKpY397. Finally, we showed that when a transient mechanical cue is provided, and coupled to changes in compliance, normal and non-metastatic cells respond preferentially to the transient cue. However, the metastatic cells neither sensed changes in compliance, nor did they respond to the transient stimulation. Together these results show that a cells ability to produce mechanical force, and sense extracellular mechanical forces, progressively decrease with the gain of metastatic characteristics.

Share

COinS