Zena Werb (1945–2020)

Zena Werb, renowned cancer biologist, passed away on 16 June. She was 75 years old. Zena was recognized internationally in the fields of proteolysis, development, and inflammation in breast cancer. Her studies of the development of the mammary gland and its neoplastic conversion during the initiation and progression of breast cancer revolutionized the fields of development and tumor biology and metastasis. Zena also served as a mentor and role model for myriad scientists. Zena was born in the Bergen-Belsen concentration camp in Germany in March 1945. Her parents had been forced to separate during World War II, but after a fortunate reunion, they moved to Canada in 1948. Zena earned a bachelor's degree in biochemistry and physiology from the University of Toronto in 1966 and a Ph.D. in cell biology from the Rockefeller University in New York City in 1971. She conducted postdoctoral research at the Strangeways Research Laboratory in Cambridge, United Kingdom, where she studied matrix metalloproteinases (MMPs)—a type of enzyme that breaks down proteins—and then she taught briefly at Dartmouth College in New Hampshire. In 1976, she launched her own laboratory at the University of California, San Francisco (UCSF), where she would spend the rest of her career, most recently as professor and vice-chair in the department of anatomy and the associate director for basic science at the UCSF Helen Diller Family Comprehensive Cancer Center. Through her pioneering work, Zena demonstrated the critical roles of MMPs in tissue functions during development and in disease. In the late 1970s and early 1980s, emerging evidence suggested that the extracellular proteins, which were targets of the lytic activity of MMPs, were providing not just structural support for cells but also cues that directly influence cellular signaling and behavior. These interactions between cells and extracellular proteins were suspected to be both dynamic and reciprocal. Zena elegantly showed that when cells bind to the extracellular protein fibronectin through a specific cell-surface receptor, intracellular signaling changes and the cell's production of MMPs increases. This critical piece of data demonstrated the bidirectional nature of interactions between cells and their extracellular environment (i.e., dynamic reciprocity). Knowing that a complete understanding of MMPs would require the study of the complex biology of a variety of organs and conditions, Zena immersed herself in the biology of bone, mammary and salivary glands, embryonic development, wound healing, and then cancer. When the cancer field was coalescing around the notion that MMP inhibitors might prevent tumor metastasis, Zena was one step ahead. She knew that this strategy would wreak havoc on normal tissue function and potentially exacerbate the disease and also that metastasis was much more involved than simple protease-assisted breaching of basement membranes. Zena's research provided a molecular and mechanistic framework for understanding how the extracellular matrix contributed to tissue morphogenesis and remodeling and the tumor microenvironment. Her ground-breaking proposals required both courage and insight. In recognition of her pioneering work, she received the Excellence in Science Award from the Federation of American Societies for Experimental Biology, the E. B. Wilson Medal awarded by the American Society for Cell Biology (ASCB) “for far-reaching contributions to cell biology over a lifetime in science,” and the ASCB Sandra K. Masur Senior Leadership Award. In 2010, Zena was elected to the National Academy of Sciences. I (M.B.) became a close friend and collaborator of Zena's in 1987. I (N.B.) met Zena when I was a postdoctoral fellow in M.B.'s lab; Zena was a co-mentor for our work on cell death and the extracellular matrix. We both remember how excited Zena was about every experiment, regardless of success or failure. She had a passion for exploration and an ability to distill highly complex biological questions into manageable and testable hypotheses. Sharing knowledge with students was a thrill for Zena. When she taught, her mesmerizing encyclopedic knowledge was on full display. Those who did not know Zena personally were sometimes intimidated by her direct style, which was evident in her keynote lectures and her questions to other presenters. However, her eagerness to ask the difficult questions and her expectation of thoughtful answers were rooted in her passion for good science. Those of us who were fortunate to know Zena personally found her to be kind-hearted and generous. She was never too busy to provide advice to the many who sought her input. She was sincerely interested in her mentees and loved to engage in lively discussions with colleagues, always showing an interest that extended beyond their ideas to their personal well-being. Her support for students and colleagues was well recognized: The American Association for Cancer Research and its Women in Cancer Research member group gave her the Charlotte Friend Memorial Lectureship for her meritorious contributions to the field of cancer research and her work advancing women in science. UCSF also honored her with a Lifetime Achievement in Mentoring Award. Zena's extraordinary career and research were complemented by her humility and humanity. She will be remembered for her original, creative, and fearless thinking, which led to her seminal work demonstrating how the extracellular environment influences the function of normal and malignant cells. Her rich legacy supporting the careers of others will live on in the scientists she mentored.