The microenvironment around cells contains an abundance of information. This includes localized signals from adjacent cells and the surrounding extracellular matrix, as well as soluble molecules such as hormones and growth factors. Collectively, these signals constitute the tissue context, and the behavior of every cell is profoundly influenced by the specific combination of signals presented to it. Functionally normal cells respond to these signals by organizing into structures that serve the body, filtering the blood in the kidney, digesting and internalizing nutrients in the intestine, and producing milk in the breast. Cancer cells react to their tissue context quite differently, by continuing to grow and proliferate when they should not, by ceasing their productive functions and taking on dangerous new properties, and by separating from the surrounding cells and disseminating to distant locations in the body. Most existing cancer therapies target the consequences of the tumor cell genetic mutations, but these are limited by the ability of the tumor cells to develop drug resistance. Recent studies show that manipulating the microenvironment can block tumor progression and even revert tumors despite their mutations; this alternative approach provides many new avenues for cancer therapy.

Dissecting the distinct microenvironmental signals and understanding how they are integrated by the cells necessitates careful reproduction of the tissue context in a manner that allows for investigations of cellular response at the molecular level. My laboratory approaches this problem through the use of designer three-dimensional culture systems that reveal the intrinsic properties of the cells: normal cells develop into functional tissue structures, but tumor cells grow and proliferate into amorphous, invasive cell masses. We have focused this approach on breast cancer, studying how normal breast cells develop into functional mammary glands, and learning how these processes go awry in the tumor context.