|Title||Deconstructing Signaling in 3 Dimensions.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Rubashkin MG, Ou G, Weaver VM|
|Date Published||2014 Mar 20|
Cells in vivo exist within the context of a multicellular tissue, where their behavior is governed by homo- and heterotypic cell-cell interactions, the material properties of the extracellular matrix, and the distribution and accessibility of various soluble and physical factors. Yet, most of the methods currently used to study and manipulate cellular behavior in vitro sacrifice physiological relevance for experimental expediency. The fallacy of such approaches to biological investigation has been highlighted by the recent development and application of three dimensional culture models to cell biology, which have revealed striking phenotypic differences in cell survival, migration, and differentiation in otherwise seemingly identical cells simply by varying culture conditions. These perplexing findings beg the question: what constitutes a three dimensional culture and why do cells behave so differently in a two versus a three dimensional culture format? In the following review, we dissect the fundamental differences between two and three dimensional culture conditions. We begin by establishing a basic definition of what "three dimensions" means at different biological scales and discuss how dimensionality influences cell signaling across different length scales. We identify which three dimensional features most potently influence intracellular signaling and distinguish between conserved biological principles that are maintained across culture conditions and cellular behaviors that are sensitive to microenvironmental context. Finally, we highlight state of the art molecular tools amenable to the study of signaling in three dimensions under conditions that facilitate deconstructing cell signaling in a more physiologically relevant manner.