Senior Advisor to the Laboratory Director
Lawrence Berkeley National Laboratory
Death from breast cancer occurs due to metastasis of cancer cells from the primary tumor in the breast to distant vital organs. For metastasis to occur, cancer cells must escape their tissue microenvironment, enter the blood or lymphatic system where they travel to distant sites, such as bone, brain or lung, and establish themselves in a new niche. In some instances this can occur very early in the disease process and the disseminated tumor cells can remain dormant for years or decades even after treatment of the primary tumor. What causes the disseminated tumor cells to awaken is poorly understood. Thus, new culture models, as well as in vivo correlates, are needed to dissect mechanisms behind tumor cell dormancy and awakening.
Dr. Bissell’s laboratory recently developed a model that mimics many of the components of the metastatic niche observed in vivo. Since they found that disseminated tumor cells in vivo are located on or near blood vessels, Dr. Bissell’s team developed an organotypic model consisting of either bone marrow or lung stromal niches, and made microvasculature-like branches consisting of endothelial cells. They saw that they could recapitulate the behavior of tumor cells in vivo (cover story in Nature Cell Biology, July 2013 issue).
Each and every cell in the body is surrounded by a microenvironment, between which there exists a mutual exchange of information that is absolutely required for the development and maintenance of tissues and organs. This exchange, being dynamic, changes continuously depending on the physiological state of the cell, guiding not only development, but also mediating growth, repair, homeostasis, immunity, and all other tissue-specific functions. How the many different types of cells comprising the breast interact with each other and their microenvironment to prevent, or even promote, cancer is still quite mysterious.
Their observations create a new paradigm of how tumor cells become dormant and how they lose dormancy as well as providing us with clues to possible pathways for prevention and therapy. Dr. Bissell’s team is now poised to ask additional and timely questions. First, how do the tumor cells get out in the first place? Secondly, how can this model be used to discover a way to maintain dormancy and also prevent metastasis? Thirdly, what is the role of recently discovered exosomes (tiny packages of cell-derived lipid vesicles found in body fluids and tissues and which may be important players in establishing the metastatic niche) in these processes? The latter will be done in collaboration with the laboratory of David Lyden at Weill Cornell Medical School. Dr. Bissell’s team intends to use their current knowledge and models to get closer to clinical applications.
In a second project, Dr. Bissell will be collaborating with fellow BCRF grantee, Dr. Laura Esserman (University of California, San Francisco), to focus on ductal carcinoma in situ (DCIS). Each and every cell in the body is surrounded by a microenvironment, between which there exists a mutual exchange of information that is absolutely required for the development and maintenance of tissues and organs. This exchange, being dynamic, evolves continuously depending on the physiological state of the cell, guiding not only development, but also mediating growth, repair, homeostasis, immunity, and all other tissue-specific functions. How the many different types of cells comprising the breast interact with each other and their microenvironment to prevent, or even promote, cancer is still quite mysterious.
In this study, Drs. Bissell and Esserman seek to better understand the earliest malignant changes in cells lining the milk ducts, the architecture of these early DCIS lesions, and the types and functions of cells in these lesions by first gaining a deeper appreciation for the complexity of the normal breast. They plan to fully characterize every cell type within the normal breast, sort them, and maintain them in culture for future studies. Once each of these different cell populations are identified and separated, the investigators will study how they might differ on a gene-transcript level. They will sequence the RNA within each cell population and apply bioinformatic techniques to identify patterns of similarity and difference within each population. Once there is a better understanding of the full catalogue of cells and their gene transcript signatures in the normal breast, Drs. Bissell and Esserman will use a similar approach in studying the relative cellular makeup of DCIS. Through this approach, they expect to gain a fuller understanding of the role of the different cellular components in normal physiology and
Dr. Bissell continues her studies related to metastasis. Biological mechanisms that contribute to the initial tumor cell dissemination and the awakening of dormant cells at the metastatic site are poorly understood. Because cells must escape their primary site and colonize a new distant site within another tissue, much focus has been given to enzymes that are capable of degrading the proteins of the extracellular matrix. One such group of enzymes, called Matrix Metalloproteinases (MMPs), is a family of enzymes collectively capable of degrading all of the proteins within the extracellular matrix. Much of the MMP research has been aimed at targeting the catalytic properties of MMPs for tumor therapy. However, these strategies have not been successful. Dr. Bissell’s team found that domains other than the catalytic domain have function in cellular invasion and tissue morphology and has been investigating as potential targets for therapy. They also have been investigating also novel mechanisms of MMP regulation, and in this past year have found that heparanase, an enzyme that degrades a component within the extracellular matrix called heparin, may also regulate the function of some MMPs. The researchers are using well established three-dimensional cell culture developed previously in the laboratory as well as their newly developed co-culture model of the microvascular niche (Ghajar et al Nat Cell Biol, 2014) to investigate the role of the microenvironment, MMPs and exosomes in breast tumor cell metastasis and release from dormancy. These studies will provide new strategies for the development of therapeutic targets for breast cancer.
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.