obituary Zena Werb 1945–2020 nlike 30 years ago, when the notion of tumor cells being regulated by Ucell-extrinsic mechanisms was akin to heresy, the tumor microenvironment (TME) is now recognized as a hallmark of cancer, with a broad community of researchers focusing on how it regulates malignant transformation, metastasis and therapy response. We owe this evolution in thinking to several scientific giants, but perhaps none more impactful in changing the storyline than Zena Werb, our intellectually fearless colleague, beloved mentor and generous friend, who died suddenly on 16 June 2020 at the age of 75. Zena was a professor and vice chair in the Department of Anatomy at the University of California San Francisco (UCSF) for over 40 years and was the associate director for basic science at the UCSF Helen Diller Family Comprehensive Cancer Center. Her foundational work on macrophage physiology, the extracellular matrix (ECM), mammary gland development, breast cancer and tumor-associated inflammation made Zena Werb as a graduate student at Rockefeller University, circa 1971. Credit: Rockefeller Grad – News her one of the most respected researchers and Notes. June 1971 Vol 2. No 10. in the world. Zena’s contributions led to numerous awards and honors, including election to the National Academy of John T. Dingle at the Strangeways Research that Zena forged an enduring collaboration Sciences and the American Association Laboratory, in Cambridge, England, she with Mina J. Bissell, who introduced her to for Cancer Research, presidency of the began investigating a new (at the time) mammary gland development and cancer. American Society of Cell Biology, the E.B. family of proteolytic enzymes secreted by Together they published innovative research Wilson Medal from the American Society fibroblasts, called matrix metalloproteinases that changed the fields of cell biology and of Cell Biology and the Paget-Ewing Award (MMPs). This class of ECM-remodeling cancer, including studies on how ECM from the Metastasis Research Society. enzymes would comprise another remodeling regulates mammary gland However, Zena, as a devoted mentor and cornerstone of her life’s work. After starting branching morphogenesis and involution, a fierce advocate for junior faculty and her own lab at Dartmouth Medical School, stem cell behavior, and cancer cell invasion particularly women, took special pride in the Zena relocated to UCSF in 1976, where and metastatic dissemination. This pivotal UCSF Lifetime Achievement in Mentoring she quickly established her reputation as collaboration also launched the careers Award, which she received in 2015. Thus, a rigorous and prolific scientist. Much of numerous trainees, including Nancy the story of Zena Werb and the TME is also of her early independent research focused Boudreau, Leif Lund, Andre Lochter, the story of her dedicated mentoring. on fibroblast and macrophage MMPs, a Farrah Kheradmand, Derek Radisky, Zena was born in 1945 in the nd she and her first postdoctoral fellow, Bryan Welm, Mark Sternlicht, Laurie Bergen-Belsen Nazi concentration camp Michael J. Banda, were the first to purify Littlepage and Valerie M. Weaver, many in Germany. After the war, her family and characterize MMP12. of whom are recognized as leaders in their emigrated to Canada, and she grew up in Her research on MMPs and their fields. Zena and Mina loved to challenge a rural community, where she attended targets led her to study ECM remodeling prevailing dogma. Among their notable a one-room schoolhouse. Following her and resultant cellular behavior, including work from this period was demonstrating undergraduate studies, Zena conducted cell proliferation and survival. Some of that collagenolytic enzymes lead to her graduate research with Zanvil A. her seminal work laid the framework the generation of oxygen radicals, and Cohn at Rockefeller University, focusing for new fields of research investigating that ECM remodeling regulates growth on lipid metabolism in macrophages. the microenvironmental regulation of factor receptor and integrin signaling Despite being biochemically inclined, Zena developmental processes, tissue homeostasis and controls cell polarity, differentiation, was enthralled when she first observed and disease pathogenesis, including cancer. proliferation and death. Among their macrophages moving in real time under the Establishing these new areas was interwoven more groundbreaking discoveries were the microscope — an experience that laid the with launching the careers of some of findings that MMP overexpression causes foundation for her later love of cell biology, her other early trainees, including James epithelial mesenchymal transition and innate immunity and intravital microscopy. McKerrow, Steven Frisch and Caroline genomic instability in non-transformed During her postdoctoral training with Alexander. It was also during this time frame mammary epithelial cells, and that MMP NATURE CANCER | VOL 1 | AUGUST 2020 | 753–754 | www.nature.com/natcancer 753 obituary overexpression is sufficient to induce tumors Bryan Welm, Andrew Ewald and Mikala to worried senior trainees), as well as in the normal mouse mammary gland. Egeblad to study cell invasion during tickets to local museums, the symphony Another critical collaboration was with mammary gland branching morphogenesis or opera, and Zena’s exceptional cooking. Douglas Hanahan. Together with their and cancer. This work yielded new She maintained contact with her mentees trainees Thiennu Vu, Gabriele Bergers insights into underlying mechanisms and as they transitioned into independent and Lisa Coussens, they published a series striking similarities between the invasive positions, and in many instances the of highly influential papers showing that programs of normal mammary epithelial mentoring relationships blossomed when MMP9 is secreted by macrophages, cells and those of breast cancer cells, as into deep kinships and productive mast cells or osteoclasts, it promotes she predicted. When intravital imaging of collaborations — such as those we three angiogenesis during normal development tumors revealed that non-tumor cells were experienced with her. With her passing, we and cancer. These reports coincided with far more motile than neoplastic cells were, grieve the loss of our cherished mentor and the development of MMP inhibitors Zena realized that the highly motile cells collaborator, and our loyal and unfailingly for cancer therapy. Nevertheless, Zena were monocytes and neutrophils. With honest friend. Science has lost an original, recognized early that some functions of Mikala Egeblad and another instrumental indefatigable cell biologist and TME MMPs also paradoxically protect against collaborator, Matthew Krummel, she researcher. But we remind ourselves that malignancy, and that the same is true refocused her work toward understanding although Zena was big-hearted, she was for many TME-derived factors that both the contributions of innate immune cells to not sentimental. We can picture her telling promote and inhibit neoplastic progression the resistance of tumors to therapy. us “Now, get on with it! Science needs by context-dependent mechanisms. When In the past several years, Zena was you, and there’s a whole new generation MMP-inhibitor efficacy was not realized in increasingly determined to understand the of trainees who need mentoring.” So we the clinic, Zena turned to using MMPs as mechanisms that regulate metastasis. With will listen to our dear mentor, roll up our tools for understanding biology rather than postdoctoral fellows Devon Lawson and sleeves, nurture our mentees (sadly with as therapeutic targets. This strategy served Kai Kessenbrock, she embraced single-cell our more pedestrian cooking) and follow as the foundation for mechanistic studies sequencing to reveal that breast cancer the data. We — and so many others — addressing the role of chronic inflammation metastases are initiated by stem-like cells, carry some of her within us, ensuring that in cancer, as discussed in a highly cited while also using the technique to compare her wisdom, fearlessness and kindness Nature article coauthored by Lisa Coussens cancer cells with normal breast epithelial remain, to become part of the fabric within and Zena in 2002. cells — an ever-present theme in her which we pursue the scientific questions Zena was scientifically fearless, routinely research. Until the end, Zena remained we seek to answer. ❐ reinventing herself, while basing her highly focused not only on understanding research decisions on rigorous scientific metastasis but also on identifying new Mikala Egeblad 1, Lisa M. Coussens2 and facts. She was excited when findings biomarkers and therapies, using her Valerie M. Weaver 3 ✉ were contrary to accepted dogma and encyclopedic knowledge of the ECM and 1Cancer Center, Cold Spring Harbor Laboratory, especially when they went against her inflammation, and her understanding of Cold Spring Harbor, NY, USA. 2Department of Cell, own expectations. She often said “the data normal development. Developmental and Cancer Biology, Oregon Health are the data, and you follow the data.” Zena’s quirky personality endeared Sciences University, Portland, OR, USA. 3Department Beyond steadfastly urging her mentees to her to mentees, whether they were of Surgery, University of California, San Francisco, follow their data wherever they led, she lab members, junior faculty or senior San Francisco, CA, USA. encouraged them to adopt or develop new colleagues. Many were treated as family ✉e-mail: [email protected] technological approaches as needed. One and were nurtured with scientific wisdom such example was her early adoption of and witty remarks (“stressed is desserts Published online: 3 August 2020 intravital imaging, which she used with spelled backwards” was a favorite line https://doi.org/10.1038/s43018-020-0101-z 754 NATURE CANCER | VOL 1 | AUGUST 2020 | 753–754 | www.nature.com/natcancer.