Z Werb

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (405)3765.7 Total impact

  • [Show abstract] [Hide abstract]
    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: 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 01/2014; 9(5):e96408. · 3.53 Impact Factor
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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. · 12.69 Impact Factor
  • Science 09/2013; 341(6151):1186-8. · 31.20 Impact Factor
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    Nature medicine 09/2013; 19(9):1104-9. · 27.14 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; · 5.88 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
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    ABSTRACT: Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression. Accordingly, miR-29b is enriched in luminal breast cancers and loss of miR-29b, even in GATA3-expressing cells, increases metastasis and promotes a mesenchymal phenotype. Mechanistically, miR-29b inhibits metastasis by targeting a network of pro-metastatic regulators involved in angiogenesis, collagen remodelling and proteolysis, including VEGFA, ANGPTL4, PDGF, LOX and MMP9, and targeting ITGA6, ITGB1 and TGFB, thereby indirectly affecting differentiation and epithelial plasticity. The discovery that a GATA3-miR-29b axis regulates the tumour microenvironment and inhibits metastasis opens up possibilities for therapeutic intervention in breast cancer.
    Nature Cell Biology 01/2013; · 20.76 Impact Factor
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    ABSTRACT: Mammary epithelial stem cells are vital to tissue expansion and remodeling during various phases of postnatal mammary development. Basal mammary epithelial cells are enriched in Wnt-responsive cells and can reconstitute cleared mammary fat pads upon transplantation into mice. Lgr5 is a Wnt-regulated target gene and was identified as a major stem cell marker in the small intestine, colon, stomach, and hair follicle, as well as in kidney nephrons. Here, we demonstrate the outstanding regenerative potential of a rare population of Lgr5-expressing (Lgr5(+)) mammary epithelial cells (MECs). We found that Lgr5(+) cells reside within the basal population, are superior to other basal cells in regenerating functional mammary glands (MGs), are exceptionally efficient in reconstituting MGs from single cells, and exhibit regenerative capacity in serial transplantations. Loss-of-function and depletion experiments of Lgr5(+) cells from transplanted MECs or from pubertal MGs revealed that these cells are not only sufficient but also necessary for postnatal mammary organogenesis.
    Cell Reports 01/2013; · 7.21 Impact Factor
  • Science 01/2013; 341(6151):1186-1188. · 31.03 Impact Factor
  • Jonathan Chou, Zena Werb
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    ABSTRACT: Mitra and colleagues analyzed microRNA expression profiles of fibroblasts isolated from ovarian cancer patients, searching for dysregulated microRNAs in the stromal compartment of human cancer. They found that decreased miR-31 and miR-214 and increased miR-155 expression can reprogram normal fibroblasts into tumor-promoting cancer-associated fibroblasts. They identified CCL5, a protumorigenic chemokine that is highly expressed in tumors, as a key target of miR-214, thus showing that microRNA perturbation in the stromal microenvironment can affect tumor growth. Cancer Discov; 2(12); 1078-80. ©2012 AACR.
    Cancer Discovery 12/2012; 2(12):1078-80. · 15.93 Impact Factor
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    ABSTRACT: Like other tissue injuries, bone fracture triggers an inflammatory response, which plays an important role in skeletal repair. Inflammation is believed to have both positive and negative effects on bone repair, but the underlying cellular mechanisms are not well understood. To assess the role of inflammation on skeletal cell differentiation, we used mouse models of fracture repair that stimulate either intramembranous or endochondral ossification. In the first model, fractures are rigidly stabilized leading to direct bone formation, while in the second model, fracture instability causes cartilage and bone formation. We compared the inflammatory response in these two mechanical environments and found changes in the expression patterns of inflammatory genes and in the recruitment of inflammatory cells and osteoclasts. These results suggested that the inflammatory response could influence skeletal cell differentiation after fracture. We then exploited matrix metalloproteinase 9 (MMP9) that is expressed in inflammatory cells and osteoclasts, and which we previously showed is a potential regulator of cell fate decisions during fracture repair. Mmp9(-/-) mice heal stabilized fractures via endochondral ossification, while wild type mice heal via intramembranous ossification. In parallel, we observed increases in macrophages and T cells in the callus of Mmp9(-/-) compared to wild type mice. To assess the link between the profile of inflammatory cells and skeletal cell fate functionally, we transplanted Mmp9(-/-) mice with wild type bone marrow, to reconstitute a wild type hematopoietic lineage in interaction with the Mmp9(-/-) stroma and periosteum. Following transplantation, Mmp9(-/-) mice healed stabilized fractures via intramembranous ossification and exhibited a normal profile of inflammatory cells. Moreover, Mmp9(-/-) periosteal grafts healed via intramembranous ossification in wild type hosts, but healed via endochondral ossification in Mmp9(-/-) hosts. We observed that macrophages accumulated at the periosteal surface in Mmp9(-/-) mice, suggesting that cell differentiation in the periosteum is influenced by factors such as BMP2 that are produced locally by inflammatory cells. Taken together, these results show that MMP9 mediates indirect effects on skeletal cell differentiation by regulating the inflammatory response and the distribution of inflammatory cells, leading to the local regulation of periosteal cell differentiation.
    Bone 09/2012; 52(1):111-119. · 4.46 Impact Factor
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    ABSTRACT: Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I.
    Proceedings of the National Academy of Sciences 08/2012; 109(39):E2595-604. · 9.81 Impact Factor
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    ABSTRACT: The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers. SIGNIFICANCE: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.
    Cancer Discovery 06/2012; 2(7):638-51. · 15.93 Impact Factor
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    ABSTRACT: There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.
    The Journal of clinical investigation 06/2012; 122(7):2661-71. · 15.39 Impact Factor
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    ABSTRACT: Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.
    Cancer cell 04/2012; 21(4):488-503. · 25.29 Impact Factor
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    ABSTRACT: The nature and site of tumor-antigen presentation to immune T cells by bone-marrow-derived cells within the tumor microenvironment remains unresolved. We generated a fluorescent mouse model of spontaneous immunoevasive breast cancer and identified a subset of myeloid cells with significant similarity to dendritic cells and macrophages that constitutively ingest tumor-derived proteins and present processed tumor antigens to reactive T cells. Using intravital live imaging, we determined that infiltrating tumor-specific T cells engage in long-lived interactions with these cells, proximal to the tumor. In vitro, these cells capture cytotoxic T cells in signaling-competent conjugates but do not support full activation or sustain cytolysis. The spatiotemporal dynamics revealed here implicate nonproductive interactions between T cells and antigen-presenting cells on the tumor margin.
    Cancer cell 03/2012; 21(3):402-17. · 25.29 Impact Factor

Publication Stats

50k Citations
3,765.70 Total Impact Points

Institutions

  • 2013
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1977–2013
    • University of California, San Francisco
      • • Department of Anatomy
      • • Department of Neurological Surgery
      • • Division of Hospital Medicine
      • • Department of Pathology
      • • Department of Surgery
      San Francisco, CA, United States
  • 2011–2012
    • The University of Manchester
      • Paterson Institute for Cancer Research
      Manchester, England, United Kingdom
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2010–2012
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 2002–2011
    • Baylor College of Medicine
      • Department of Medicine
      Houston, TX, United States
    • University of Pennsylvania
      • Institute for Medicine and Engineering
      Philadelphia, PA, United States
  • 2005–2010
    • The University of Tokyo
      • Institute of Medical Science
      Tokyo, Tokyo-to, Japan
  • 2008
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1982–2008
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2007
    • Rensselaer Polytechnic Institute
      • Center for Biotechnology and Interdisciplinary Studies
      Troy, NY, United States
  • 1991–2007
    • Lawrence Berkeley National Laboratory
      • Life Sciences Division
      Berkeley, CA, United States
  • 2003–2006
    • Beth Israel Deaconess Medical Center
      • • Department of Medicine
      • • Division of Matrix Biology
      Boston, MA, United States
    • Juntendo University
      • Atopy (Allergy) Research Center
      Tokyo, Tokyo-to, Japan
    • Weill Cornell Medical College
      • Division of Hematology/Medical Oncology
      New York City, NY, United States
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 2002–2006
    • Cornell University
      • • Department of Genetic Medicine
      • • Department of Medicine
      Ithaca, NY, United States
  • 2000–2005
    • University of North Carolina at Chapel Hill
      • Department of Dermatology
      Chapel Hill, NC, United States
    • Rigshospitalet
      • Finsen Laboratory
      Copenhagen, Capital Region, Denmark
  • 2001
    • University of Wisconsin, Madison
      • McArdle Laboratory for Cancer Research
      Madison, MS, United States
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1998
    • University of California, Los Angeles
      • Brain Research Institute
      Los Angeles, CA, United States
  • 1995
    • American University of Beirut
      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