Mina J. Bissell, PhD

2012-2013 BCRF Project:
The metastatic cascade is typically illustrated as a linear process. However, there is increasing evidence that breast tumors disseminate very early during progression and that these disseminated tumor cells may lie dormant in recipient organs for years. While there are a number of models to study invasion and metastasis, there are very few models of how or why cancer cells remain dormant for years and then "wake up" (recur) unexpectedly.

Dr. Bissell is leading a study on tumor dissemination and dormancy, the underlying mechanisms of which researchers know very little. She and her team believe that these two steps-tumor dissemination and dormancy-are the rate-limiting stages of tumor progression. New organotypic models are needed to understand the dynamics of invasion, dormancy and recurrence, because no cell is an island.

Dr. Bissell's laboratory is well poised to develop new and complex 3D culture models in conjunction with laboratory models to shed new light on the triangle of metastasis, dormancy, and recurrence, with special emphasis on the role of a newly discovered class of mediators of metastasis referred to as "exosomes." In this latter area, Dr. Bissell's laboratory will share research results and discuss their synergistic work with a world-renowned expert in this area, Dr. David Lyden (Weill Cornell Medical College), with whom they have an existing collaboration.

Mid-year Progress: Metastasis of breast cancer cells requires that the cells must escape their breast environment, enter the blood system, exit the blood system and find a new niche, where they remain dormant until waken up by as yet poorly understood regulators and form tumors at sites distant from the original tumor. In order for cells to escape the primary tumor site, travel through the blood supply and exit into a new tissue, the cells must degrade components of the extracellular matrix at several steps. It is universally thought that proteinases called Matrix Metalloproteinases (MMPs) are involved in this process. This was considered such a proven fact that it had become a dogma.

Clinical trials were begun a number of years ago to inhibit MMP enzyme activity to halt the invasiveness of tumors cells. Unfortunately, the approach of globally inhibiting the proteolytic activity of the MMPs failed badly and these trials were unsuccessful. This implied that scientists did not yet understand the complexities of MMP-dependent invasiveness in tumor cells. Dr. Bissell then hypothesized that other regions of the molecule may also be involved in the process of invasion in addition to the enzymatic region. If so, this meant that clinical trials failed because they targeted the presumed but not the actual target. An important MMP that plays a critical role in mammary gland involution (i.e. restructuring the gland after birth and weaning of the new born) is called MMP3. By making packaging viruses that contained different regions of the MMP3 and infecting mammary cells with it, scientists could test which region was important for invasion in 3-dimensional gels of collagen, a large extracellular molecule that is important in functional differentiation of mammary gland. Dr. Bissell's team has found that indeed their hypothesis is correct for MMP3. Since this MMP3 is secreted to the outside of the cells, they subjected the extracellular medium to mass spectrometry and isolated protein complexes. They now have identified several proteins that bind to MMP3 via a region of the MMP3 called the hemopexin domain. This region is distinct from the enzyme activity region, and Dr. Bissell's team is currently validating the functional role of one of these binding partners that appears to be involved in MMP3's invasive function.

Bio:
Mina J. Bissell, PhD, is an international authority on the role that the cell microenvironment plays in cancer formation and progression. She has been recognized for her lifetime contributions to the fields of breast cancer research, the enhanced role of extracellular matrix (ECM) and the nucleus environment to gene expression in normal and malignant tissues. These works have ushered and have changed some central paradigms that have strengthened the importance of context in the development of cancer.

Dr. Bissell received her master's degree in Bacteriology & Biochemistry and doctorate in Microbiology & Molecular Genetics from Harvard Medical School. She has been awarded numerous honors, most recently BCRF's Jill Rose Award for distinguished biomedical research (2011) and the Lifetime Achievement Award by the Lawrence Berkeley National Laboratory (2012). Dr. Bissell will deliver the Distinguished Lectureship in Breast Cancer Research at the 2012 San Antonio Breast Cancer Symposium, the world's largest annual meeting in the field, this December.

Dr. Bissell was elected Fellow of the National Academy of Science and the Royal Society of Chemistry in 2010. She is currently a member of the Committee for Cancer Post-GWAS Initiative of the National Institutes of Health/National Cancer Institute and on the Scientific Advisory Board of European Union's Innovative Medicines Initiative program. In addition, Dr. Bissell is on the editorial board of several journals, including Journal of Cellular Biochemistry, Journal of Clinical Investigation, Breast Cancer Research, International Journal of Cancer, and Cancer Microenvironment.