In one of her most well-known experiments, Mina J. Bissell showed that integrin β1-inhibitory antibody treatment of mammary tumor cells (right) leads to a reversion of the malignant phenotype (center) and a closer resemblance to normal cells (left); from Weaver, V.M., et al., (1997) J. Cell. Biol. 137, 231-45.
Now, quite fascinated with how the surrounding tissue architecture might influence these events, Bissell decided to switch to a model more relevant to the human condition. “Fortunately, I had a wonderful postdoc, Joanne Emerman, who had done her thesis on mammary glands, so we decided to focus on that, since the mammary gland undergoes a lot of developmental changes and is frequently associated with cancer. And her help in getting our work underway was quite invaluable.”
(Because her own background was primarily bacterial genetics, enzymology and metabolism, Bissell also recognizes two other great postdocs, Rick Schwarz and Glenn Hall, who used their graduate student expertise in collagen and basement membranes, respectively, to mentor her in those areas.)
The key to success, though, would be finding a suitable method to study microenvironment interactions in detail. “Obviously, two-dimensional studies in petri dishes would be limited, but some experiments would be impractical in mouse models as well,” she says.
Her solution was to develop an ingenious three-dimensional culture matrix that resembled a natural extracellular matrix and enabled mammary cells to form spatially relevant structures like a real mammary gland, initially in mice (with postdoc Mary Helen Barcellos-Hoff) and then in human breast (with Ole Petersen, a young professor in Denmark). She states that this is, by no means, a perfect system, but Bissell and her lab continually are working on improving their three-dimensional matrices.
Since then, Bissell and her group have been using these three-dimensional models to explore how cells and the surrounding extracellular matrix interact to shape cell behaviors such as polarity, migration and proliferation; it’s a concept she has termed a “dynamic reciprocity” in signaling between the extracellular matrix, transmembrane receptors, the cytoskeleton, the nucleus and the chromatin.
This has led to some real eye-opening discoveries, perhaps best highlighted by a series of studies in the late 1990s, in which Bissell’s group demonstrated that antibodies against the β1-integrin receptor lowered EGF signaling and altered the behavior of cancerous breast cells to a more normal phenotype; conversely, adding matrix metalloproteinases to degrade the three-dimensional matrix could induce invasive phenotypes in otherwise nonmalignant breast cells.
And, these eye-opening results would not have been evident in any two-dimensional system.