Published OnlineFirst August 26, 2020; DOI: 10.1158/0008-5472.CAN-20-2602 CANCER RESEARCH | OBITUARY Zena Werb, Ph.D, “Queen of the Matrix”: In Memoriam (1945–2020) Shahin Rafii1 and David Lyden2 To understand Zena’s beginnings is to understand the essence of journey. Zanvil allowed Zena to be the driver of her own project, which who Zena was as a person, mentor, matriarch, and as a world-class she chose to be on the role of macrophages regulating cholesterol scientist. We are fortunate to have crossed paths with her. metabolism. This freedom in turn helped foster her independence and Zena’s achievements are remarkable, considering the hardships confidence in pursuing an academic career in cell biology. She she faced as she navigated through the adventurous journey of life. continued her training in a postdoctoral position with John Dingle She endured a difficult childhood, some life-threatening illnesses, at Strangeways Research Laboratory in Cambridge, United Kingdom. and challenging transitions from Europe to Canada and then to the There, she shifted away from macrophage research and instead studied United States to evolve into one of the most decorated renowned fibroblasts. She determined through her investigations that fibroblasts scientists of our time. Zena was an imposing figure of a woman that produce matrix metalloproteinases (MMP) and revealed how this demanded respect, with a wicked sense of humor and brilliance that family of enzymes influences collagen as one of the main components rubbedoffonanyonethatwasnearher.Shewasapowerhouseof of the extracellular matrix (ECM). This pioneering work ignited her principles to reckon with, and she was a woman of authority to learn continued interest in not only the functional role of MMPs on the from. outside of cells, but also their influence on signaling pathways within Zena’s very start was harrowing and heart-wrenching—she was cells. This was the start of her pivotal research in MMPs and ECMs. born at the Bergen–Belsen concentration camp in Germany at the Eventually, she found her way to the University of California, San endoftheWorldWarII.Zena’s mother and father had been Francisco, where she built a distinguished career focused mainly on separated during the war and scores of relatives on both sides of her MMPs as critical regulators in the tumor microenvironment, partic- famiy had been killed. Fortunate to have survived, her mother, ularly of breast cancer. expecting to be reunited with Zena’s father, traveled with one- Her legendary partnership with Mina Bissell at the Lawrence month-old Zena back to Poland, their homeland. Discovering that Berkeley National Laboratory for over 40 years led to their powerhouse Zena’s father was actually in a displaced persons camp in Italy, collaboration in ECM research that dominated that field for so long. Zena’s mother then began her journey with Zena, often by foot, Surprisingly, it took decades for Zena and Mina to be fully recognized through the Alps to finally reunite the family. Eventually, they for their work in ECM biology, which demonstrated that the ECM can immigrated to Canada where Zena’s parents bought a farm, where control the “phenotypic and functional outcome” of tumor cells and Zena threw bales of hay and fed the cows. Zena’s experience of influence tumor progression and metastasis. displacement and of overcoming hardships and her life lesson in Zena got along best with scientists who were not afraid to think perseverance all helped to mold her identity. outside the box and with those who built a career from original ideas Insprired by her father’s interests in science, she was determined to despite expected skepticism from the scientific community. pursue a scientific career, which began at the age of 16 years old at the This is how we first were introduced to Zena. She generously À À University of Toronto, obtaining a bacherlor’s degree in biochemistry provided the MMP9 / mice that were instrumental in our work on and biophysics. This led her to pursue a doctorate at Rockefeller endothelial progenitor cells and myeloid precursors for tumor vascu- University in New York, working with her mentor the late Zanvil larization and premetastatic niche formation. We were really “na€ve Cohn. There, she was first introduced to the field of macrophages, a cell scientists” then (and maybe still are), but she believed in us and our type that dominated her curiosity throughout her entire scientific work from the moment we first met. She encouraged us to believe in ourselves and our ideas. We know she respected our work and we appreciated that immensely. In addition to our exciting scientific exchanges, we enjoyed each other’s company and she would laugh 1Division of Chief Regenerative Medicine, Weill Cornell Medicine, New York, New a lot with us. She also enjoyed being back in New York, one of her York. 2Departments of Pediatrics and Cell and Developmental Biology, Drukier favorite places. She relished the cultural scene, with visits to museums, Institute for Children’s Health and Meyer Cancer Center, New York, New York. concerts, and plays (but not Broadway). We remember fondly our Corresponding Authors: Shahin Raffii, Division Chief Regenerative Medi- adventures going to the opera, seeing Carmen all together, an evening cine, Weill Cornell Medicine, 1300 York Avenue, Room A-863, New York, NY of smiles and laughter. 10065. E-mail: srafi[email protected]; and David Lynden, Departments of Zena is one of a few scientists who could continue to reinvent Pediatrics and Cell and Developmental Biology, Drukier Institute for Chil- herself every few years, tackling multiple inquiries. Among her dren’s Health and Meyer Cancer Center, Belfer Research Building, 413 E. 69th Street, BB-1228-Box 284, New York, New York 10021. latest reinventions, she established herself as one of the drivers of [email protected] intravital imaging of trafficking macrophages at primary tumor sites. She often commented, “Thetumorcellsareboringstanding Cancer Res 2020;80:1–2 still for the most part; however, the macrophages are much more doi: 10.1158/0008-5472.CAN-20-2602 interesting, making all the moves within the tumor microenviron- Ó2020 American Association for Cancer Research. ment.” Beyond the primary tumor, her latest work involved AACRJournals.org | OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst August 26, 2020; DOI: 10.1158/0008-5472.CAN-20-2602 Rafii and Lyden examining a macrophage subpopulation in the lung capable of She was a great mentor and collaborator with many other notable engulfing newly arrived metastatic tumor cells, thereby preventing scientists, such as Lisa Coussens (immune landscape), Val Weaver metastasis development. (ECM/stiffness), Gerard Evans (molecular signatures), Susan Fisher She was certainly respected by the scientific community, as reflected (placental biology), and Jay Debnath (autophagy). by her most notable honors: She was not only a role model for women in science, but she equally supported the careers of men as well. In our own experience, she made * Elected Member of the Institute of Medicine of the National sure to encourage us along our paths to becoming professors. Her Academies (2002), friends were women and men, young and old, of diverse backgrounds. * Elected Fellow of the American Academy of Arts and Sciences She only judged individuals on their scientific merit. And she could be (2003), tough and critical if she did not think you had original ideas. * E. B. Wilson Medal from the American Society of Cell Biology Zena’s wish was always that she wanted to go on a “high” while still (2007), actively working in the lab. This is a wish that came true—unfortu- * Elected Member of the National Academy of Sciences (2010, which nately, too soon. Just the night before her death, she was planning to she was especially proud to be a part of), resubmit a grant with Val Weaver. She spoke with Val, asking her to get * Elected Fellow of the Academy of the American Association for her parts of the grant ready as soon as possible. Cancer Research (2019). Besides her scientific prowess, Zena valued family, happiness, and truth. She looked for the good in each person. She nurtured many She received many other honors, commemorated by coins and friendships with her generous and giving soul. She was a judge of good sculpted pieces. She would often joke about placing these items in a character. She valued character over pedigree and scientific status. “ ’ dresser drawer, never to be seen again. She would quip, Why can tI Most importantly, she loved art, music, opera, and travel to exotic ” win some of the monetary awards instead? For this year, Zena was destinations. At the end of every year she would send her close – selected to receive the Paget Ewing Award, the highest award given by colleagues and friends a “Zena Year End Letter,” which summarized the Metastasis Research Society, for her major contributions in the her adventurous journeys. We always looked forward to reading her fi metastasis eld. letters, which were honest, funny, educational, and incredibly futur- She was never afraid to speak her mind at conferences, at lab istic. In a way, Zena wanted to pass on her wisdom and send us fi meetings, or one on one while eating a ne dinner (and always with messages of hope, optimism, and how to enjoy life. a glass of good wine). For those who listened carefully, this led to Zena always knew there was a chance that her name would not to be opportunities to pursue new avenues of research, mainly related to the remembered among scientific circles. Her hope, instead, was that her fi tumor microenvironment. Her forthrightness is best exempli ed by contributions would live on in those she trained, mentored, and her actions.