Effects of cancerous mutations on mechanosensing of cells Public

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The ability of cells to sense mechanical cues is essential for normal cell function, tissue development, and wound healing. Aberrant sensitivity to mechanical cues from the extracellular environment has been observed in cancer cells and many other types of diseases. Abnormal activities/expression of several proteins have been identified as hallmarks of cancer. Understanding how these proteins regulate the mechanosensing ability of cells would further explore the potential usage of these proteins as targets for cancer therapeutics. In this study, we characterized the effects of three prominent cancer markers used in pharmacology–vimentin, PTEN and KRAS–on cells’ mechanosensing behavior. We observed that lowering the level of vimentin expression in fibroblasts reduces the cell traction force but does not affect mechanosensing ability. These results suggest that the function of vimentin in mechanosensing is facilitating the force transmission inside cells. By studying the effects of knocking out PTEN and overexpressing KRAS in MCF-10A breast epithelial cells, we investigated the impacts of cancer-associated pathways PI3K/AKT and Ras/MAPK on mechanosensing. Knocking out PTEN abolished mechanosensing ability and inhibited the formation of stress fibers–bundles of actin filaments –which is critical for force transmission and hence mechanosensing. Overexpressing KRAS promotes stress fiber formation but did not significantly affect the mechanosensing of MCF-10A. Furthermore, KRAS overexpression overturns the effects of PTEN knockout on stress fiber and rescues the mechanosensing ability of PTEN knockout cells. Our results suggest that both the PI3K/AKT pathway (upregulated via PTEN loss) and the KRAS/MAPK pathway (upregulated via KRAS overexpression) impact mechanosensing through their effects on the actin cytoskeleton. More importantly, we unveiled that the crosstalk of these two pathways co-modulates mechanosensing and cell migration.

  • etd-4246
Defense date
  • 2020
Date created
  • 2020-09-01
Resource type
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