2007 - Mina J. Bissell
University of California
Berkeley, CA
Motivation:
The 2007 Pezcoller Foundation-AACR International Award for Cancer Research is given to Mina J. Bissell, PhD, an extraordinarily accomplished cell biologist whose scientific discoveries in basic cancer research have had an enormous impact on our understanding of the mechanism by which the extracellular matrix (ECM) and the microenvironment regular gene expression and the stability of the differentiated state in normal and malignant tissues. Dr. Bissell pioneered the field of the role of the microenvironment, ECM, and the three-dimensional (3D) tissue structure in differentiation and cancer.
In a series of papers published in Science, Nature, and Journal of Cell Biology, which are now referred to as milestones in cancer, Dr. Bissell showed that even a potent oncogenic virus such as Rous sarcoma (RSV) is tumorigenic only in the right context: when tissue structure is disrupted as in 2D cultures, mass transformation ensues. She showed further that even in hatched chicks, wounding is a co-carcinogen for RSV, providing some of the first concrete links between inflammation, TGF-β, and cancer.
Dr. Bissell extended these findings to epithelial tumor biology (Journal of Theoretical Biology). She was among the first to propose that there is a reciprocal interaction between the cell, the chromatin, and ECM, with each profoundly and dynamically influencing the other. She put forth an encompassing vision that 3D tissue architecture, cell-ECM, and cell-cell interactions and cytoplasmic and nuclear organization are all functionally integrated and are powerful parameters in the regulation of gene expression, homeostasis, and growth in normal and malignant cells. Her laboratory then devised the appropriate assays and performed the critical experiments to validate these concepts. Dir. Bissell’s group initially chose one single milk protein, β-casein gene and the interacting transcription factors. More recently, they are studying the exciting area of how ECM signaling is involved in global chromatin organization, histone acetylation, and other chromatin remodeling events.
Dr. Bissell has had a number of prolonged and productive collaborations. With Dr. Zena Werb at UCSF, she demonstrated the critical importance of the matrix metalloproteinases (MMPs) that degrade ECM and other adhesion molecules; in papers in Journal of Cell Biology, Development, American Journal of Pathology and Cell, they showed that such persistent degradation in engineered mice could lead to mammary tumors. In a recent and important paper in Nature, her group examined the mechanism of how degradation of ECM could cause mammary tumors. They showed that activation of MMPs can lead to genomic instability via induction of alternative splicing of molecules involved in cytoskeletal organization. With Drs. Ole Petersen and Lone Ronnov-Jessen at the Panum Institute, Denmark they extended the 3D models to human cells and provided a versatile and rapid assay for distinguishing normal and malignant cells. Her laboratory then showed that malignant human breast epithelial cells containing large numbers of mutations and oncogenic alterations can revert to a polar structural organization and become phenotypically normalized in 3D and lose its ability to form tumors in vivo if signaling by β1-integrin or a number of other signaling inhibitors is down-modulated. Each modulation in turn was shown too reciprocally regulate other signaling receptors. Remarkably, they showed that these cross talks occur mainly in 3D and not in 2D. Her laboratory then showed that irrespective of growth rate and mutational status, tissue polarity controls resistance to apoptotic agents used in the clinic—a finding that has important implications for understanding dormancy and cancer therapy. In a recent paper in Science, Dr. Bissell’s group has designed new high throughput and quantitative assays for understanding mammary branching and invasion. In collaboration with the Petersen laboratory, her laboratory is working with combinatorial platforms to identify how adult stem cell fate is guided by the microenvironmental cell.
For over three decades, Dr. Bissell’s elegant studies have revealed that the critical unit of biological function is the integrated signaling circuit provided by the tissue (organ) architecture. She has systematically looked beyond single cell showing that the interaction of cells with each other and with ECM and the rest of the microenvironment influence cell proliferation, survival, morphogenesis, differentiation, and cell fate – all processes that go awry in cancer. These studies highlight innovative and imaginative approaches combined with rigor and persistence. The concepts she has developed are fundamental to normal tissue morphogenesis and cancer, and the impact of her work is profound for how we view biological regulation. Like many great scientists throughout history, Dr. Bissell has taken an original and refreshed approach that has produced revolutionary new concepts.
Dr. Bissell received her bachelor’s degree in chemistry with honors from Radcliffe-Harvard College. She received her PhD in microbiology/molecular genetics from Harvard University. She began her career as a Milton Fellow at Harvard University in 1969, subsequently serving as an American Cancer Society Fellow at UCB. In 1972 she joined the Staff of Lawrence Berkeley National Laboratory becoming a Senior Scientist in 1976. She served as the Director of the Cell and Molecular Biology Division from 1988-1992; as the Director of all Life Sciences from 1992-2002; as the Associate Director of Biosciences from 1995-2002; and upon stepping down as Director, was named Distinguished Scientist and Senior Advisor to the Laboratory Director on Biology in 2002, positions she currently holds. Dr. Bissell also serves as a member of the faculty of three graduate groups at the University of California, Berkeley, and a member of Cancer Center at UCSF. Dr. Bissell received numerous recognitions and awards for her scientific achievements including her elections as a Fellow of the American Academy for the Advancement of Science, a member of the Institute of Medicine of the National Academy of Sciences, and a member of the American Academy of Arts and Sciences. She has been honored both by the DOD (first Innovator Award) and the DOE (first Distinguished Fellow in Biosciences) and received honorary doctorates from Pierre and Marie Curie University in Paris and the University of Copenhagen. A member of the American Association for Cancer Research since 1988, Dr. Bissell served on its Board of Directors from 1999 to 2001 and received the AACR-G.H.A. Clowes Memorial Award in 1999.
