Building on four decades of research, Mina Bissell, Distinguished Scientist in Biological Systems and Engineering (BSE) Division and her colleagues have demonstrated a dynamic reciprocity between the extracellular matrix (ECM) and cell nucleus for tissue-specific gene expression. Using the 3D ECM gel to study signaling from outside the cell to the nucleus they have unraveled a dozen different pathways critical for the formation of phenotypically normal breast tissue. The signaling between the ECM and the nucleus is pivotal, bidirectional, and intricate. In two papers published in eLife this week, Bissell and Dan Fletcher, BSE faculty scientist and Purnendu Chatterjee Professor and Chair of Bioengineering at UC Berkeley, shed new light on how the extracellular matrix communicates with breast cells to generate nitric oxide, forming a loop that influences the pathway a single cell takes to form breast tissue.