Access Type

Open Access Embargo

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Karen A. Beningo

Abstract

Cell invasion is an important process utilized by cancer cells to progress through the metastatic cascade to form deadly secondary tumors. This process can be influenced by the wide array of biomechanical forces that cancer cells within and around a tumor face in their microenvironment. It is not completely clear how these forces, either alone or simultaneously combined with other forces, can impact the metastatic capacity of cancer cells. To address this, we have utilized an in vitro mechano-invasion assay to mimic a transient tugging force that exists within the tumor microenvironment caused by the remodeling of the extracellular matrix by highly contractile cells, such as myofibroblasts. Furthermore, we have used a novel dual-stimulation assay to compare the response between normal, non-metastatic and metastatic cells to two simultaneous mechanical stimuli. Our results show that transient mechanical stimulation leads to increased invadopodia maturation in highly invasive fibrosarcoma cells, as shown by confocal microscopy and the activity of invadopodia-associated matrix-degrading enzymes. This increase in invadopodia maturation is caused by the down-regulation of the integrin β3 mechano-receptor, a decrease in p21-activated kinase 1 (PAK1) activity and an increase in cofilin activity. Additionally, when normal and non-metastatic cells are simultaneously stimulated with a change in substrate compliance and mechanical tugging, they preferentially responded to the tugging force over compliance. The metastatic cells did not preferentially respond to either mechanical cue. Together, these data indicate that highly invasive cells can upregulate their cell invasion in response to transient mechanical stimulation through increasing the maturation of invadopodia. Also, when metastatic cells are simultaneously given conflicting mechanical cues, they can preferentially ignore them, whereas non-metastatic cells do not. This suggests that there is a major interplay between the mechanical forces that exist near a tumor, the physiological nature of the cancer cells themselves and the level of metastatic capacity of these cells.

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