An in vitro correlation of metastatic capacity and dual mechanostimulation.

Indrajyoti Indra,Karen A Beningo,Alexander N Gasparski

doi:10.1371/journal.pone.0207490

Abstract

Cells are under the influence of multiple forms of mechanical stimulation in vivo. For example, a cell is subjected to mechanical forces from tissue stiffness, shear and tensile stress and transient applied strain. Significant progress has been made in understanding the cellular mechanotransduction mechanisms in response to a single mechanical parameter. However, our knowledge of how a cell responds to multiple mechanical inputs is currently limited. In this study, we have tested the cellular response to the simultaneous application of two mechanical inputs: substrate compliance and transient tugging. Our results suggest that cells within a multicellular spheroid will restrict their response to a single mechanical input at a time and when provided with two mechanical inputs simultaneously, one will dominate. In normal and non-metastatic mammary epithelial cells, we found that they respond to applied stimulation and will override substrate compliance cues in favor of the applied mechanical stimulus. Surprisingly, however, metastatic mammary epithelial cells remain non-responsive to both mechanical cues. Our results suggest that, within our assay system, metastatic progression may involve the down-regulation of multiple mechanotransduction pathways.

Highlights

Mechanotransduction is a mechanism that regulates cellular behaviors during development [1, 2] tissue morphogenesis [3, 4], wound healing [5], and cancer cell invasion [6, 7]
Designing an assay for the simultaneous application of two mechanical stimuli The purpose of this study was to understand how cellular sensing of substrate compliance and applied mechanical cues is affected with metastatic progression
The non-metastatic and metastatic breast cancer cell lines of the murine panel spheroids were placed at the border of the two compliances and the applied stimulus was generated by the rotating magnet

Summary

Introduction

Mechanotransduction is a mechanism that regulates cellular behaviors during development [1, 2] tissue morphogenesis [3, 4], wound healing [5], and cancer cell invasion [6, 7]. With the assistance of other signaling molecules working in concert, mechanical signals are converted into molecular responses. Examples of these responses include actin polymerization, integrin activation, tyrosine phosphorylation and the secretion of signaling molecules for survival, adhesion, proliferation and cell migration [12,13,14]. These responses arise upon the application of a single mechanical stimulus. Our understanding of what occurs to these mechanotransduction responses when multiple mechanical stimuli are applied simultaneously is currently limited. It has previously been reported that endothelial cell migration is positively influenced when fluid shear stress is applied to cells on compliant substrates, but not on harder substrates [15]

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