(557a) Cancer Cell Migration in 3D

Although much is known about mechanical and spatial signal transduction in cells migrating on conventional two-dimensional (2D) substrates, drastic functional differences are apparent in the molecular machinery driving cell migration through more physiologically-relevant, fibrilar, three-dimensional (3D) environments.  Taking an inside-out approach to understanding the function of cell adhesion proteins in 3D cell migration, we use shRNA constructs to silence expression of a variety of focal adhesion proteins and demonstrate that external dimensional cues are critical to protein localization and signaling.  We show that 3D cell motility parameters are not predicted by the same parameters in 2D.  Likewise, the focal adhesion protein zyxin plays a distinctive role in the temporal and dimensional aspects of cell trajectories in 3D and 1D microenvironments, but not on 2D substrates.  Lastly, taking an outside-in approach, we demonstrate that changes in 3D matrix microstructure alone modulates modes of cell motility.  This occurs via microstructure induced spatial positioning of protrusions and matrix metalloproteinase (MMP) activity.  Thus, cell motility may only be abrogated by small molecule inhibition of MMPs in distinct matrix microstructures.

References

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Fraley et al. Nature Cell Biology 13: 5-7 (2011)

Fraley et al. Nature Communications 3:719-731 (2012)