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Binding of extracellular matrix (ECM) proteins to integrin receptors initiates intracellular signaling events that are essential for the differentiation and survival of epithelial cells. However, the propagation and processing of these signals also depend on the cells acquiring an appropriate three-dimensional morphology and polarity after contact with the ECM. In fact, even if adhesion to the ECM is maintained but subsequent cellular organization and polarity are impaired, epithelial cells fail to fully differentiate and become susceptible to apoptotic stimuli. Studies using three-dimensional tissue culture models with reconstituted basement membranes not only demonstrate the central role of tissue organization for differentiation and survival, but also emphasize how acquiring this organized polarized phenotype can override a number of genetic changes that would otherwise disrupt normal tissue function.