Zena Werb

University of California, San Francisco, San Francisco, California, United States

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Publications (451)4159.46 Total impact

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    ABSTRACT: Tubulogenesis is fundamental to the development of many epithelial organs. Although lumen formation in cysts has received considerable attention, less is known about lumenogenesis in tubes. Here we utilized hepatocyte growth factor induced tubulogenesis in MDCK cells, which form tubes enclosing a single lumen. We report the mechanism that controls tubular lumenogenesis and limits each tube to a single lumen. Knockdown of 114RhoGEF, a guanine nucleotide exchange factor for RhoA, did not perturb the early stages of tubulogenesis induced by hepatocyte growth factor. However, this knockdown impaired later stages of tubulogenesis, resulting in multiple lumens in a tube. Inhibition of Rho Kinase or myosin IIA, which are downstream of RhoA, led to formation of multiple lumens. We studied lumen formation by live cell imaging, which revealed that inhibition of this pathway blocked cell movement, suggesting that cell movement is necessary for consolidating multiple lumens into a single lumen. Lumen formation in tubules is mechanistically quite different from lumenogenesis in cysts. Thus, we demonstrate a novel pathway that regulates directed cell migration and single lumen formation in epithelial tube morphogenesis.
    Journal of Cell Science 10/2015; DOI:10.1242/jcs.172361 · 5.43 Impact Factor
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    ABSTRACT: Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.
    Nature 09/2015; 526(7571). DOI:10.1038/nature15260 · 41.46 Impact Factor
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    ABSTRACT: Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue. Since the mammary gland (MG) is the only organ developing predominantly after birth, we utilized it as a powerful system to study adaptive immune regulation of organogenesis. We found that antigen-mediated interactions between mammary antigen-presenting cells and interferon-γ (IFNγ)-producing CD4+ T helper 1 cells participate in MG postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement. IFNγ then affects luminal lineage differentiation. This function of adaptive immune responses, regulating normal development, changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance and cancer transformation.
    Developmental Cell 08/2015; 34(5). DOI:10.1016/j.devcel.2015.07.015 · 9.71 Impact Factor
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    ABSTRACT: Purpose To develop a strategy of achieving targeted collection of endothelial cells (ECs) by endovascular methods and analyzing the gene expression profiles of collected single ECs. Methods and results 134 ECs and 37 leukocytes were collected from four patients' intra-iliac artery endovascular guide wires by fluorescence activated cell sorting (FACS) and analyzed by single-cell quantitative RT-PCR for expression profile of 48 genes. Compared to CD45+ leukocytes, the ECs expressed higher levels (p < 0.05) of EC surface markers used on FACS and other EC related genes. The gene expression profile showed that these isolated ECs fell into two clusters, A and B, that differentially expressed 19 genes related to angiogenesis, inflammation and extracellular matrix remodeling, with cluster B ECs have demonstrating similarities to senescent or aging ECs. Conclusion Combination of endovascular device sampling, FACS and single-cell quantitative RT-PCR is a feasible method for analyzing EC gene expression profile in vascular lesions.

  • Cancer Research 08/2015; 75(15 Supplement):4724-4724. DOI:10.1158/1538-7445.AM2015-4724 · 9.33 Impact Factor
  • Matilda F Chan · Zena Werb ·
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    ABSTRACT: The cornea is an excellent model system to use for the analysis of wound repair because of its accessibility, lack of vascularization, and simple anatomy. Corneal injuries may involve only the superficial epithelial layer or may penetrate deeper to involve both the epithelial and stromal layers. Here we describe two well-established in vivo corneal wound models: a mechanical wound model that allows for the study of re-epithelialization and a chemical wound model that may be used to study stromal activation in response to injury (Stepp et al., 2014; Carlson et al., 2003).
    07/2015; 5(13):e1516.
  • Matilda F Chan · Zena Werb ·
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    ABSTRACT: The accessibility and transparency of the cornea makes it a good tissue model for monitoring immunological responses using in vivo real time imaging analysis (Lee et al., 2010; Tan et al., 2013). These corneal qualities have also allowed for high-resolution in vivo imaging of non-ocular tissue transplanted into the anterior chamber of the mouse eye (Speier et al., 2008a; Speier et al., 2008b). This protocol was adapted from Speier (2008) to successfully assess real-time in vivo myeloid cell dynamics in wounded corneas of c-fms-EGFP mice (Chan et al., 2013). Macrophage colony-stimulating factor (CSF-1) regulates the differentiation and proliferation of cells of the mononuclear phagocyte system. The activity of CSF-1 is mediated by the CSF-1 receptor that is encoded by c-fms (Csf1r) protooncogene. The c-fms gene is expressed in macrophage, trophoblast cell lineages, and to some extent granulocytes. In the c-fms-EGFP mice EGFP, enhanced green fluorescent protein, is driven under the Csf1r, colony stimulating factor 1 receptor, promoter and highlights myeloid cells (Sasmono et al., 2003). This protocol can be further adapted to image other transgenic mice expressing fluorescent proteins.
    07/2015; 5(13):e1517.
  • Zena Werb · Pengfei Lu ·
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    ABSTRACT: The tumor microenvironment plays an essential role in various stages of cancer development. This environment, composed of the extracellular matrix, fibroblasts, endothelial cells, and cells of the immune system regulates the behavior of and co-evolve with tumor cells. Many of the components, including the innate and adaptive immune cells, play multifaceted roles during cancer progression and can promote or inhibit tumor development, depending on local and systemic conditions. Interestingly, a strategy by which tumor cells gain drug resistance is by modifying the tumor microenvironment. Together, understanding the mechanisms by which the tumor microenvironment functions should greatly facilitate the development of new therapeutic interventions by targeting the tumor niche.
    The Cancer Journal 07/2015; 21(4):250-3. DOI:10.1097/PPO.0000000000000127 · 4.24 Impact Factor
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    ABSTRACT: The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1-Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras-ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR-RasGRP1 and EGFR-SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma.
    Nature Cell Biology 05/2015; 17(6). DOI:10.1038/ncb3175 · 19.68 Impact Factor
  • Ann F Chambers · Zena Werb ·
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    ABSTRACT: IntroductionMost cancer deaths are due to metastasis—the spread of cancer from its site of origin to distant, vital organs—and the physiological damage caused by tumor growth in those organs. While the broad outlines of the process of metastatic spread are known, much of the details of the process remain poorly understood. To continue to improve cancer survival rates, we must face and tackle the problems inherent to metastatic disease. Cancers that are detected early, before they are believed to have spread to other organs, are generally treated with more success than cancers that are metastatic at diagnosis. However, even cancers that are detected early will recur in some patients, but our ability to predict which individuals will have recurrences is limited. Thus, adjuvant therapy is often given to patients with early-stage disease who are believed as a group to be at risk for recurrence, leading to overtreatment of some patients to benefit a subset of them and possibly failing to tr ...
    Journal of Molecular Medicine 03/2015; 93(4). DOI:10.1007/s00109-015-1269-z · 5.11 Impact Factor
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    Vicki Plaks · Niwen Kong · Zena Werb ·
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    ABSTRACT: Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 03/2015; 16(3). DOI:10.1016/j.stem.2015.02.015 · 22.27 Impact Factor
  • Amy-Jo Casbon · Marja Lohela · Zena Werb ·
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    ABSTRACT: Myeloid cells contribute to increased malignancy and poor prognosis in breast cancer. We demonstrate that anti-CSF-1R therapy depletes a cell population sharing characteristics of tumor-associated macrophages (TAMs) and dendritic cells (DCs). Intravital imaging combined with cellular characterization has refined our understanding of anti-CSF-1R therapy on the tumor microenvironment.
    OncoImmunology 03/2015; 4(6):e1008871. DOI:10.1080/2162402X.2015.1008871 · 6.27 Impact Factor
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    Kai Kessenbrock · Chih-Yang Wang · Zena Werb ·
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    ABSTRACT: Since Gross and Lapiere firstly discovered matrix metalloproteinases (MMPs) as important collagenolytic enzymes during amphibian tadpole morphogenesis in 1962, this intriguing family of extracellular proteinases has been implicated in various processes of developmental biology. However, the pathogenic roles of MMPs in human diseases such as cancer has also garnered widespread attention. The most straightforward explanation for their role in cancer is that MMPs, through extracellular matrix degradation, pave the way for tumor cell invasion and metastasis. While this notion may be true for many circumstances, we now know that, depending on the context, MMPs may employ additional modes of functionality. Here, we will give an update on the function of MMPs in development and cancer, which may directly regulate signaling pathways that control tissue homeostasis and may even work in a non-proteolytic manner. These novel findings about the functionality of MMPs have important implications for MMP inhibitor design and may allow us to revisit MMPs as drug targets in the context of cancer and other diseases.
    Matrix Biology 02/2015; 48. DOI:10.1016/j.matbio.2015.01.022 · 5.07 Impact Factor
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    ABSTRACT: Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.
    Proceedings of the National Academy of Sciences 01/2015; 112(6). DOI:10.1073/pnas.1424927112 · 9.67 Impact Factor
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    ABSTRACT: The kynurenine pathway of tryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiological functions remain unclear. We report that kynurenic acid, a metabolite in this pathway, functions as a regulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegans alters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis that promotes elevated feeding through enhanced serotonin release when animals re-encounter food. Upon refeeding, kynurenic acid levels are eventually replenished, ending the elevated feeding period. Because tryptophan is an essential amino acid, these findings suggest that a physiological role of kynurenic acid is in directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad range of behaviors and physiologies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 01/2015; 160(1-2):119-131. DOI:10.1016/j.cell.2014.12.028 · 32.24 Impact Factor
  • Amy-Jo Casbon · Vicki Plaks · Zena Werb ·

    Cancer Research 01/2015; 75(1 Supplement):IA09-IA09. DOI:10.1158/1538-7445.CHTME14-IA09 · 9.33 Impact Factor
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    ABSTRACT: The NET subfamily of zinc finger proteins is an important mediator during developmental processes. The evolutionary conserved zinc finger protein ZNF503/ Zeppo2 (zinc finger elbow-related proline domain protein-2; Zpo2) plays critical roles during embryogenesis. We have found that Zpo2 is expressed in adult tissue and have examined its function. We find that Zpo2 is a nuclear-targeted transcriptional repressor that is expressed in mammary epithelial cells. Elevated Zpo2 levels increase mammary epithelial cell proliferation. Zpo2 promotes cellular invasion through downregulation of E-cadherin and regulates the invasive phenotype in a Rac1-dependent manner. We detect elevated Zpo2 expression during breast cancer progression in MMTV-PyMT transgenic mouse model. Tumor transplant experiments indicated that overexpression of Zpo2 in MMTV-PyMT mammary tumor cell lines enhances lung metastasis. Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; 290(6). DOI:10.1074/jbc.M114.611202 · 4.57 Impact Factor
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    Catharina Hagerling · Amy-Jo Casbon · Zena Werb ·
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    ABSTRACT: Cells of the innate immune system have a dual role in cancer development in both tumor initiation and progression. Innate immune cells can, on the one hand, aid malignant transformation and tumor outgrowth and, on the other hand, prevent tumor progression. The innate immune system has the ability to tune the inflammatory response and is a key player in cancer-related inflammation, which can precede the development of malignancy or be induced by oncogenic changes promoting a protumor inflammatory milieu. In this review, we discuss the emerging cellular and molecular mechanisms of the innate immune system and inflammation in tumor initiation and progression, and point to the outstanding questions that remain.
    Trends in Cell Biology 11/2014; 25(4). DOI:10.1016/j.tcb.2014.11.001 · 12.01 Impact Factor
  • Caroline Bonnans · Jonathan Chou · Zena Werb ·
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    ABSTRACT: The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
    Nature Reviews Molecular Cell Biology 11/2014; 15(12):786-801. DOI:10.1038/nrm3904 · 37.81 Impact Factor
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    ABSTRACT: Tumor-infiltrating inflammatory cells comprise a major part of the stromal microenvironment and support cancer progression by multiple mechanisms. High numbers of tumor myeloid cells corre-late with poor prognosis in breast cancer and are coupled with the angiogenic switch and malignant progression. However, the specific roles and regulation of heterogeneous tumor myeloid populations are incompletely understood. CSF-1 is a major myeloid cell mitogen, and signaling through its receptor CSF-1R is also linked to poor outcomes. To characterize myeloid cell function in tumors, we combined confocal intravital microscopy with depletion of CSF-1R– dependent cells using a neutralizing CSF-1R antibody in the mouse mammary tumor virus long-terminal region-driven polyoma middle T antigen breast cancer model. The depleted cells shared markers of tumor-associated macrophages and dendritic cells (M-DCs), match-ing the phenotype of tumor dendritic cells that take up antigens and interact with T cells. We defined functional subgroups within the M-DC population by imaging endocytic and matrix metalloproteinase activity. Anti–CSF-1R treatment altered stromal dynamics and im-paired both survival of M-DCs and accumulation of new M-DCs, but did not deplete Gr-1 + neutrophils or block doxorubicin-induced myeloid cell recruitment, and had a minimal effect on lung myeloid cells. Nevertheless, prolonged treatment led to delayed tumor growth, reduced vascularity, and decreased lung metastasis. Because the myeloid infiltrate in metastatic lungs differed significantly from that in mammary tumors, the reduction in metastasis may result from the impact on primary tumors. The combination of functional analysis by intravital imaging with cellular characterization has re-fined our understanding of the effects of experimental targeted ther-apies on the tumor microenvironment. inflammation | myeloid cells | matrix metalloproteinase | CSF-1 receptor |
    Proceedings of the National Academy of Sciences 11/2014; 111(47). DOI:10.1073/pnas.1419899111 · 9.67 Impact Factor

Publication Stats

67k Citations
4,159.46 Total Impact Points


  • 1977-2015
    • University of California, San Francisco
      • • Department of Anatomy
      • • Department of Medicine
      • • Department of Pathology
      San Francisco, California, United States
    • Dartmouth–Hitchcock Medical Center
      LEB, New Hampshire, United States
  • 2004-2006
    • CSU Mentor
      Long Beach, California, United States
  • 2002-2004
    • Baylor College of Medicine
      • Department of Medicine
      Houston, Texas, United States
    • Weill Cornell Medical College
      • Department of Medicine
      New York, New York, United States
  • 2001
    • University of North Carolina at Chapel Hill
      • Department of Dermatology
      North Carolina, United States
    • University of California, Berkeley
      • Lawrence Berkeley Laboratory
      Berkeley, California, United States
  • 2000
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 1995-1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1994-1997
    • Lawrence Berkeley National Laboratory
      • Life Sciences Division
      Berkeley, CA, United States
  • 1993
    • University of Southern California
      • Center for Craniofacial Molecular Biology
      Los Ángeles, California, United States
  • 1976-1990
    • University of Oxford
      • Sir William Dunn School of Pathology
      Oxford, ENG, United Kingdom
  • 1989
    • University of San Francisco
      San Francisco, California, United States
  • 1978
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
    • Geisel School of Medicine at Dartmouth
      • Department of Medicine
      Hanover, New Hampshire, United States
  • 1971-1972
    • The Rockefeller University
      New York City, New York, United States