Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices

Abstract

Mammary gland development, functional differentiation, and homeostasis are orchestrated and sustained by a balance of biochemical and biophysical cues from the organ's microenvironment. The three-dimensional microenvironment of the mammary gland, predominantly 'encoded' by a collaboration between the extracellular matrix (ECM), hormones, and growth factors, sends signals from ECM receptors through the cytoskeletal intracellular matrix to nuclear and chromatin structures resulting in gene expression; the ECM in turn is regulated and remodeled by signals from the nucleus. In this chapter, we discuss how coordinated ECM deposition and remodeling is necessary for mammary gland development, how the ECM provides structural and biochemical cues necessary for tissue-specific function, and the role of the cytoskeleton in mediating the extra--to intracellular dialogue occurring between the nucleus and the microenvironment. When operating normally, the cytoskeletal-mediated dynamic and reciprocal integration of tissue architecture and function directs mammary gland development, tissue polarity, and ultimately, tissue-specific gene expression. Cancer occurs when these dynamic interactions go awry for an extended time.

Fig. 1

A scheme showing the principle of dynamic reciprocity between cells and their extracellular microenvironment. Cell-cell and cell-ECM interactions induce cascades of both physical and biochemical signals which transmit from the cell membrane to the nucleus via the cytoskeleton. These signals modulate organization of both the cytoskeleton and chromatin organization, leading to changes in cellular architecture and gene expression which in turn influence the microenvironment. Blue arrows represent the bidirectional transmission of physical and biochemical signals. (modified from [1])

Fig. 2

A cartoon showing that the ECM provides architectural and biochemical cues necessary for tissue-specific function. Aggregating mammary epithelial cells in suspension exposes prolactin receptor and allows transient STAT5 activation in response to prolactin stimulation, but this is not sufficient to induce casein and WAP expression. Laminin-dependent biochemical signals, in conjunction with prolactin signaling, induce the sustained STAT5 activation required for casein expression. Additionally, laminin-induced reorganization of cellular architecture is necessary for the formation of polarized acini, which allows for the expression of WAP