Disease Models & Mechanisms 3, 513-516 (2010) doi:10.1242/dmm.006338 © 2010. Published by The Company of Biologists Ltd A MODEL FOR LIFE The extracellular matrix and disease: an interview with Zena Werb Zena Werb’s pioneering efforts brought recognition to the idea that the extracellular matrix has a profound influence in determining cell fate. Here, she discusses how a ‘rocky’ start in geophysics led her to a career that is changing the way we think about cancer. I started college. Ironically, earthquakes veryone is influenced by what became an important part of my life as a goes on around them, and cells resident of San Francisco, but I didn’t realise are much the same. The signalling this would be the case then. Back in college, Emolecules and support structures I wanted to go on a summer geology field of the extracellular matrix (ECM) course to the Rockies. I was one of the top direct many aspects of normal cell two students in my class, but they wouldn’t behaviour, including shape, migration and let me go because I was female – they said survival. However, the ECM can also play that there were not the proper facilities on a role in the development and progression the site for women. Instead, I found a DMM of disease. For example, a cell does not summer job in the field and actually got become cancerous on its own – together paid for the experience I gained, which with intrinsic changes, oncogenesis is would not have happened if I’d been encouraged by cues from the surrounding allowed into the course. However, I worried milieu. Furthermore, the aberrant survival that if it was impossible for me to be out to study when I became a graduate of cancer cells is propagated by signals included in the profession at the level of a student at the Rockefeller. Again, I hit a received from the microenvironment, and summer course, I might always encounter roadblock. The person in charge of X-ray malignancy depends on the ability of cells roadblocks that would inhibit my ability to crystallography at the Rockefeller was to crawl along ECM proteins to invade work. The field of geology clearly had Gerry Edelman, who was notoriously foreign tissues. strong prejudices. difficult to work with. He won the Nobel Following decades of research based on I decided that biochemistry made more Prize in 1972 for his work defining the isolated cells in culture dishes, scientists are sense. Back in the 60s, the field of bio- structure of antibodies, but I knew that I now rethinking how the microenvironment chemistry was still quite male oriented, but did not want to work with someone with that surrounds cells in vivo instructs devel- I never had the sense that taking a course his reputation. Instead, I did a rotation in opment, differentiation, inflammation and could be a barrier for me. Even if there was Zanvil Cohn’s lab. Within the first few days, cancer. Many of Zena Werb’s early findings some prejudice, it seemed that the quality I saw macrophages moving in real time Disease Models & Mechanisms led to this shift in thinking, and she is now of my research and my ability to do it under the microscope, and I was hooked! I creating new technologies that allow sci- would allow me to advance. Also, there hadn’t thought about the biological part of entists to look directly into the cancer were already a few female faculty in bio- biomedical sciences until that moment and, microenvironment. By following an inter- chemistry. all of a sudden, I realised that it was the esting and sinuous path, Zena Werb I was also drawn to the physical aspects most fascinating aspect of it. We were uncovered a great deal about the complex of the field. My main study focus was bio- actually watching the biology happen. I nature of interactions between cells and chemistry, although I minored in chemistry. went on to work on macrophages as a their support structures. My second summer job during college was thesis project. at the Ontario Cancer Institute, where I I later went to England for my postdoc. You intended to be a geolophysics major used optical rotary dispersion and other As a graduate student, I had worked mainly in your earliest days at the University of kinds of physical techniques to determine on how macrophages are involved in lipid Toronto. What pre-empted your switch molecular structures. I found working with metabolism and how they might contribute to biochemistry and physiology? structures very fascinating. to atherosclerosis. Now, I wanted to learn I was interested in geophysics, under- more about proteins. I moved to standing situations like earthquakes, when Did your interest in physical structures Strangeways Research Laboratory in and the techniques that define them Cambridge, England, and examined stimulate your interest in the ECM? lysosomes and enzyme function in fibro - Zena Werb is Professor and Vice-Chair in the Department of Anatomy at the University of My interest in the ECM came later. My blasts. The person working next to me was California, San Francisco (UCSF). interest in physical techniques drew me to focused on matrix metalloproteinases, and e-mail: [email protected] X-ray crystallography, which is what I set I began to wonder if my cells might make Disease Models & Mechanisms 513 A MODEL FOR LIFE Zena Werb these proteinases. When we tested this, it might be strongly influenced by submicron levels in terms of its structure turned out that fibroblasts did generate increased understanding of the ECM? and its function. The ECM differs on one metalloproteinases that allow them to I think that there are many diseases that side of the cell versus the other. So, the remodel their surrounding support struc- people will one day consider to be ECM interaction of a cell with the ECM may vary tures. Suddenly, I had to think about my diseases. There is a strong interest in the across it, with adhesions in one area but not cells in the context of their extracellular ECM with respect to its contribution to in another. This heterogeneity does not environment. I realised that we were cancer – this is one area in which the link conform well to many powerful technolo- looking at a fabulous biological system, is already recognised, even though we don’t gies, such as proteomics, microarrays or with a careful balance of signals between thoroughly understand it. The contribution genomics. These technologies do not have cells and their environment. This became of the ECM to arthritis and atherosclerosis the resolution to look at subcellular differ- my area of focus as a postdoc and later also seems fairly clear. However, the ECM ences. evolved into the basis of my research on the is probably also very important for many The ECM is also subject to many post- ECM. brain diseases. There are several other synthetic modifications. Many matrix examples where changes in the ECM may proteins are cleaved in several places and Once you realised that ECM was lead to disease, such as fibrosis and can therefore be structurally quite different, important, you incorporated it into your abnormal wound healing. Many diseases – despite their original similarities. Other work with cells. However, there is a gen- in fact most diseases – are probably ECM ECM proteins are differentially spliced and eration of literature that involved diseases. have multiple splice variants. They also get research of cultured cells that did not crosslinked to each other and to other take the ECM into account. How do you proteins. So, the alteration of one molecule think that what we are learning about the “There are many diseases can induce changes in a very complex ECM now might influence the interpre- that people will one day structure. Because the overall structure of DMM tation of cell culture studies? consider to be ECM the ECM isn’t homogeneous, the regulation What has happened, at long last, is that can be altered quite markedly by subtle many people who have been focused on the diseases” changes. These subtle changes can lead to structural aspects of the ECM are recog- cell transformation, and transformed cells nising the influence of tissue structure on One disease area that people don’t often keep making components that normal cells biology. For example, there was early think of in terms of the ECM is infection. would not make. Therefore, the structure interest in the structure of the ECM in The connection between infection and the of the resulting ECM can be very different trades such as leather tanning, which dealt ECM is not immediately clear, but, in fact, and may have a different influence on cell with skin ECM components such as three-dimensional structure influences how behaviour. collagen. But it took much longer for people bacteria and host cells respond to infection. to recognise that the functional unit in the The type of matrix that surrounds the host I hear from my colleagues that you are a body is not a cell, but a cell and the ECM inflammatory cells determines their respected mentor. What do you do to that surrounds it. The discovery of integrins responses and dictates how well they can help students and postdocs become suc- (cell-surface receptors that bind to ECM search out, find and kill invading bacteria cessful? components such as collagen and in three-dimensional space. There have I give students and postdocs as much fibronectin) in the 1980s pushed scientists been very few studies looking at the freedom as they can handle. I believe that, Disease Models & Mechanisms to look at things outside the cell.