Zena Werb

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

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Publications (415)3881.36 Total impact

  • [Show abstract] [Hide abstract]
    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. · 3.65 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 of the United States of America. 01/2015;
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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.
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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; · 4.60 Impact Factor
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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; · 12.31 Impact Factor
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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. · 37.16 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; · 9.81 Impact Factor
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    ABSTRACT: The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKCβII phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.
    Developmental cell. 10/2014;
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    ABSTRACT: Background: Breast cancer has a complex etiology that includes genetic, biologic, behavioral, environmental and social factors. Etiologic factors are frequently studied in isolation with adjustment for confounding, mediating and moderating effects of other factors. A complex systems model approach may present a more comprehensive picture of the multi-factorial etiology of breast cancer. Methods: We took a transdisciplinary approach with experts from relevant fields to develop a conceptual model of the etiology of postmenopausal breast cancer. The model incorporated evidence of both the strength of association and the quality of the evidence. We operationalized this conceptual model through a mathematical simulation model with a subset of variables, namely, age, race/ethnicity, age at menarche, age at first birth, age at menopause, obesity, alcohol consumption, income, tobacco use, use of hormone therapy (HT) and BRCA1/2 genotype. Results. In simulating incidence for California in 2000, the separate impact of individual variables was modest, but reduction in HT, increase in the age at menarche, and to a lesser extent reduction in excess BMI >30 kg/m2 were more substantial. Conclusions: Complex systems models can yield new insights on the etiologic factors involved in postmenopausal breast cancer. Modification of factors at a population level may only modestly affect risk estimates, while still having an important impact on the absolute number of women affected. Impact: This novel effort highlighted the complexity of breast cancer etiology, revealed areas of challenge in the methodology of developing complex systems models and suggested additional areas for further study.
    Cancer Epidemiology Biomarkers & Prevention 07/2014; 23(10). · 4.32 Impact Factor
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    ABSTRACT: Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad-spectrum matrix metalloproteinase inhibitor, results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naïve dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0-4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0-8.0) or GM6001 (mean, 5; 95% CI 2.0-8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord.
    PLoS ONE 05/2014; 9(5):e96408. · 3.53 Impact Factor
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    ABSTRACT: Myeloid cells are the most abundant immune cells within tumors and have been shown to promote tumor progression. Modern intravital imaging techniques enable the observation of live cellular behavior inside the organ but can be challenging in some types of cancer due to organ and tumor accessibility such as intestine. Direct observation of intestinal tumors has not been previously reported. A surgical procedure described here allows direct observation of myeloid cell dynamics within the intestinal tumors in live mice by using transgenic fluorescent reporter mice and injectable tracers or antibodies. For this purpose, a four-color, multi-region, micro-lensed spinning disk confocal microscope that allows long-term continuous imaging with rapid image acquisition has been used. Apc(Min) (/+) mice that develop multiple adenomas in the small intestine are crossed with c-fms-EGFP mice to visualize myeloid cells and with ACTB-ECFP mice to visualize intestinal epithelial cells of the crypts. Procedures for labeling different tumor components, such as blood vessels and neutrophils, and the procedure for positioning the tumor for imaging through the serosal surface are also described. Time-lapse movies compiled from several hours of imaging allow the analysis of myeloid cell behavior in situ in the intestinal microenvironment.
    Journal of visualized experiments : JoVE. 01/2014;
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    ABSTRACT: Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.
    Cell 12/2013; · 31.96 Impact Factor
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    ABSTRACT: Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.
    PLoS Biology 11/2013; 11(11):e1001712. · 11.77 Impact Factor
  • Science 09/2013; 341(6151):1186-8. · 31.48 Impact Factor
  • Science 09/2013; 341(6151):1186-1188. · 31.48 Impact Factor
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    Nature medicine 09/2013; 19(9):1104-9. · 28.05 Impact Factor
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    ABSTRACT: The tumor microenvironment includes cells such as fibroblasts, immune cells, endothelial cells, as well as extracellular matrix (ECM), proteases, and cytokines. Together, these components participate in a complex crosstalk with neoplastic tumor cells that affects growth, angiogenesis, and metastasis. MicroRNAs (miRNAs) are small, non-coding RNAs involved in post-transcriptional regulation of gene expression and have recently emerged as important players involved in regulating multiple aspects of cancer biology and the tumor microenvironment. Differential miRNA expression in both the epithelial and stromal compartments of tumors compared with normal tissue suggests that miRNAs are important drivers of tumorigenesis and metastasis. This review article summarizes our current understanding of the diverse roles of miRNAs involved in tumor microenvironment regulation and underscores the importance of miRNAs within multiple cell types that contribute to the hallmarks of cancer.
    Cell cycle (Georgetown, Tex.) 08/2013; 12(20). · 5.24 Impact Factor
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    ABSTRACT: The microenvironment provides cues that control the behavior of epithelial stem and progenitor cells. Here, we identify matrix metalloproteinase-3 (MMP3) as a regulator of Wnt signaling and mammary stem cell (MaSC) activity. We show that MMP3 overexpression promotes hyperplastic epithelial growth, surprisingly, in a nonproteolytic manner via its hemopexin (HPX) domain. We demonstrate that MMP3-HPX specifically binds and inactivates Wnt5b, a noncanonical Wnt ligand that inhibits canonical Wnt signaling and mammary epithelial outgrowth in vivo. Indeed, transplants overexpressing MMP3 display increased canonical Wnt signaling, demonstrating that MMP3 is an extracellular regulator of the Wnt signaling pathway. MMP3-deficient mice exhibit decreased MaSC populations and diminished mammary-reconstituting activity, whereas MMP3 overexpression elevates MaSC function, indicating that MMP3 is necessary for the maintenance of MaSCs. Our study reveals a mechanism by a microenvironmental protease that regulates Wnt signaling and impacts adult epithelial stem cell function.
    Cell stem cell 07/2013; · 23.56 Impact Factor
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    ABSTRACT: Corneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers α-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of MMP12(-/-) mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in MMP12(-/-) corneas by confocal imaging. We determined that the altered dynamics owed to an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration six days later, mediated by altered expression levels of chemokines CCL2 and CXCL1, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair via regulation of immune cell infiltration and angiogenesis.
    Journal of Cell Science 06/2013; · 5.33 Impact Factor
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    ABSTRACT: The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.
    Proceedings of the National Academy of Sciences 06/2013; · 9.81 Impact Factor

Publication Stats

57k Citations
3,881.36 Total Impact Points

Institutions

  • 1977–2014
    • University of California, San Francisco
      • • Department of Anatomy
      • • Department of Neurological Surgery
      • • Division of Hospital Medicine
      • • Department of Pathology
      San Francisco, California, United States
  • 2013
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2010–2012
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 2011
    • Harvard Medical School
      Boston, Massachusetts, United States
    • The University of Manchester
      • Wellcome Trust Centre for Cell-Matrix Research
      Manchester, England, United Kingdom
  • 2005–2010
    • The University of Tokyo
      • Institute of Medical Science
      Tokyo, Tokyo-to, Japan
  • 2008
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
  • 1999–2008
    • CSU Mentor
      Long Beach, California, United States
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2007
    • Rensselaer Polytechnic Institute
      • Center for Biotechnology and Interdisciplinary Studies
      Troy, NY, United States
  • 2002–2007
    • Baylor College of Medicine
      • Department of Medicine
      Houston, TX, United States
  • 1991–2007
    • Lawrence Berkeley National Laboratory
      • Life Sciences Division
      Berkeley, CA, United States
  • 2006
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, MA, United States
  • 2003
    • Weill Cornell Medical College
      • Division of Hematology/Medical Oncology
      New York City, NY, United States
    • Universität Basel
      Bâle, Basel-City, Switzerland
    • Juntendo University
      • Atopy (Allergy) Research Center
      Tokyo, Tokyo-to, Japan
  • 2001
    • University of Wisconsin, Madison
      • McArdle Laboratory for Cancer Research
      Madison, MS, United States
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 2000
    • Rigshospitalet
      • Finsen Laboratory
      Copenhagen, Capital Region, Denmark
    • University of North Carolina at Chapel Hill
      • Department of Dermatology
      Chapel Hill, NC, United States
  • 1998
    • University of California, Los Angeles
      • Brain Research Institute
      Los Angeles, CA, United States
  • 1995
    • American University of Beirut
      • Department of Biology
      Beyrouth, Beyrouth, Lebanon
  • 1993
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1992
    • Northwestern University
      • Department of Obstetrics and Gynecology
      Evanston, IL, United States
  • 1990
    • University of Oxford
      • Sir William Dunn School of Pathology
      Oxford, ENG, United Kingdom
  • 1978
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States