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Interrogating the Role of Spatial Organization in Receptor Function: Eph-Ephrin Signaling in Breast Cancer


Cells in living tissue integrate multiple signals from their environment to govern numerous aspects of both healthy and diseased behavior. The cell membrane serves as an exquisite functional filter that regulates information transmission between a cell and its surrounding environment. This viscoelastic plasma membrane, which allows lateral diffusion while restricting the orientation of signaling molecules within the plane of a phospholipid bilayer, is uniquely well suited to make sense of the myriad biochemical, mechanical, and spatial cues that constantly stimulate receptors on the cell surface. The chemical basis for the cell membrane, a fluid phospholipid bilayer, can be used to create a supported membrane that retains these properties while allowing precise control over the physical and chemical aspects of signaling molecules on the supported membrane surface.

Cell communication is critical for proper maintenance of multicellular organisms, and tumorigenesis can occur when communication is not properly controlled. Cancerous cells often display a vastly altered array of cell surface receptors compared to normal cells, and the abnormal signaling that these receptors trigger has grave consequences for the fate of the cell and the organism as a whole. The dynamics by which these receptors bind to ligands within the environment are not well understood because the cell membrane is a chemically heterogeneous and physically irregular surface that is difficult to study in vivo. Here we recapitulate signaling events that occur in live cancer cells using the supported membrane to present laterally mobile ligands to receptor-expressing human breast cancer cells.

This platform allows for precise control of the spatial organization of signaling molecules on the supported membrane surface, as well as a detailed examination of subsequent changes in signaling events within living cells. Using this approach we observe receptor reorganization responses that are strongly linked to tissue invasion and our observations reveal a mechanism by which cells respond to the spatial and mechanical aspects of their environment.

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