Zena Werb

University of California, San Francisco

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Mark D. Sternlicht

FibroGen (United States)

Laurie E. Littlepage

University of Notre Dame

Devon A. Lawson

University of California, Irvine

Mina J. Bissell

Lawrence Berkeley National Laboratory

Mikala Egeblad

Cold Spring Harbor Laboratory

Jonathan Chou

UCSF Helen Diller Family Comprehensive Cancer Center

Andrew J. Ewald

Johns Hopkins University

Hosein Kouros‐Mehr

Amgen (United States)

Audrey Brenot

Washington University in St. Louis

Paul Yaswen

University of Nevada, Reno

Cooperative Institutions

University of California, San Francisco

560

Harvard University

137

UCSF Helen Diller Family Comprehensive Cancer Center

118

National Institutes of Health

Stanford University

Howard Hughes Medical Institute

University of California, Berkeley

Inserm

University of California, San Diego

Lawrence Berkeley National Laboratory

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Epidermal Growth Factor Receptor-deficient Mice Have Delayed Primary Endochondral Ossification Because of Defective Osteoclast Recruitment

Journal of Biological Chemistry (2004)

Ke Wang Hiroaki Yamamoto Jennie R. Chin Zena Werb Thiennu H. Vu

The epidermal growth factor receptor (EGFR) and its ligands function in diverse cellular functions including cell proliferation, differentiation, motility, and survival. EGFR signaling is important for the development of many tissues, including skin, lungs, intestines, and the craniofacial skeleton. We have now determined the role of EGFR signaling in endochondral ossification. We analyzed long bone development in EGFR-deficient mice. EGFR deficiency caused delayed primary ossification of the cartilage anlage and delayed osteoclast and osteoblast recruitment. Ossification of the growth plates was also abnormal resulting in an expanded area of growth plate hypertrophic cartilage and few bony trabeculae. The delayed osteoclast recruitment was not because of inadequate expression of matrix metalloproteinases, including matrix metalloproteinase-9, which have previously been shown to be important for osteoclast recruitment. EGFR was expressed by osteoclasts, suggesting that EGFR ligands may act directly to affect the formation and/or function of these cells. EGFR signaling regulated osteoclast formation. Inhibition of EGFR tyrosine kinase activity decreased the generation of osteoclasts from cultured bone marrow cells.

Endochondral ossification

Primary (astronomy)

10.1074/jbc.m403114200

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Citations (111)

Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrin-derived signals.

The Journal of Cell Biology (1995)

Patrice Tremble C H Damsky Zena Werb

We have shown previously that the expression of collagenase is upregulated in rabbit synovial fibroblasts cultured on a substrate of antibody to the alpha 5 chain of the alpha 5 beta 1 integrin fibronectin receptor or on the 120-kD cell-binding chymotryptic fragment of plasma fibronectin, but remains at basal levels in cells plated on intact plasma fibronectin. We now have identified some of the components of a signaling pathway that couples the fibronectin receptor to the induction of collagenase transcription. We studied the control of collagenase gene expression in cells adhering to the 120-kD fragment of fibronectin, to antifibronectin receptor antibody, or to plasma fibronectin by transiently introducing promoter-reporter constructs into rabbit synovial fibroblasts before plating cells on these matrices. The constructs contained segments of the human collagenase promoter regulating transcription of chloramphenicol acyl transferase. Expression of constructs containing the -1200/-42-bp segment or the -139/-42-bp segment of the collagenase promoter inserted upstream from the reporter gene was induced to similar extents in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in fibroblasts plated on fibronectin. The expression of the construct containing the -66/-42-bp segment of the promoter was not regulated and was similar to that of the parent pBLCAT2 plasmid, suggesting that the -139/-67 region of the collagenase promoter, which contains PEA3- and AP1-binding sites, regulates the transcription of collagenase caused by integrin-derived signals. Expression of a reporter construct containing only the PEA3 and AP1 sites in the collagenase promoter (-90/-67) also increased in cells plated on the 120-kD fragment of fibronectin or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. Mutations in either the AP1 or PEA3 site of this minimal promoter abrogated its activity in cells plated on these inductive ligands. Expression of c-fos mRNA increased within 1 h of plating cells on the 120-kD fibronectin fragment or on anti-fibronectin receptor antibody, relative to that in cells plated on fibronectin. c-Fos protein accumulated in the nuclei of fibroblasts within 10 min of plating on the 120-kD fibronectin fragment. The increase in c-Fos was required for the increase in collagenase in cells plated on the 120-kD fibronectin fragment: incubation of cells with antisense, but not sense, c-fos oligonucleotides diminished both basal and induced expression of the -139/-42 collagenase promoter-reporter construct and decreased expression of the endogenous collagenase gene.(ABSTRACT TRUNCATED AT 400 WORDS)

AP-1 transcription factor

10.1083/jcb.129.6.1707

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Citations (116)

Confocal Imaging of Myeloid Cells in the Corneal Stroma of Live Mice

BIO-PROTOCOL (2015)

Matilda F. Chan Zena Werb

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.

10.21769/bioprotoc.1517

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Citations (2)

Preface

Annals of the New York Academy of Sciences (1998)

Raúl Fleischmajer RUBERT TIMPL Zena Werb

Annals

10.1111/j.1749-6632.1998.tb10101.x

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Abstract 198: Endovascular Biopsy: in vivo Brain Aneurysm Endothelial Cell Sampling and Gene Expression Analysis

Stroke (2017)

Daniel L. Cooke Van V. Halbach Steven W. Hetts Matthew R. Amans Christopher F. Dowd

Introduction: Cerebral aneurysms affect 1-6% of the population and their rupture carries significant mortality and morbidity. The paucity of data related to histopathological features of aneurysms stems largely from the risks associated with aneurysm tissue collection. We set out to establish a feasible technique to isolate viable endothelial cells (EC) and to characterize the differences in genetic expression (GE) between iliac arterial cells vs. aneurysm cells and non-ruptured vs. ruptured aneurysm cells. Methods: 10 patients (5 non-ruptured and 5 ruptured) undergoing aneurysm treatment were enrolled under IRB approval. ECs from aneurysms and iliac arteries were sampled using an appropriately sized coil and a 0.035 “J” wire respectively. Coils and wires were processed via FACS and single cell qPCR to quantify expression of 48 genes implicated in EC function and aneurysm pathogenesis. Mixed models were performed using each GE level as the outcome with multiple predictors. Unsupervised cluster analysis including: hierarchical heat-map clustering, K-medoids, principle components, cART, and self-organizing maps (SOM) were used to find cell clusters based on coordinately expressed GE. Results: 437 FACS-sorted cells were collected and 319 demonstrated CD31, CD34 and CD105 triple-positive expression. Of these, 94 were aneurysmal cells. The average number of extracted aneurysm cells per patient was 9.4 (1-24, median 6.5) with a trend for higher cell yields from ruptured aneurysms (p = 0.116). Mixed model analyses revealed a history of smoking showed the strongest associations with GE (median p-value 0.104 with 11/48 analyses p < 0.05); 5 genes significantly predicted rupture status (median p-value 0.363 with 5/48 analyses p < 0.05); and one gene significantly differentiated cell type (median p-value 0.557, with 1/48 analyses p < 0.05). SOM analysis revealed clustered GE profiles suggestive of distinct functional EC sub-populations. Conclusion: Cerebral endovascular sampling is a safe and reliable means for targeted cell collection for genetic analysis. Smoking was strongly associated with GE levels. Our analysis provides evidence that GE levels may be associated with cell type and rupture status.

CD31

10.1161/str.48.suppl_1.198

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Roles of the immune system in cancer: from tumor initiation to metastatic progression

Genes & Development (2018)

Hugo González Catharina Hagerling Zena Werb

The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

Tumor progression

10.1101/gad.314617.118

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Citations (1,702)

New functions for the matrix metalloproteinases in cancer progression

Nature reviews. Cancer (2002)

Mikala Egeblad Zena Werb

Matrix metalloproteinase inhibitor

10.1038/nrc745

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Citations (5,955)

Delineating CSF-1-dependent regulation of myeloid cell diversity in tumors

OncoImmunology (2015)

Amy-Jo Casbon Marja Lohela Zena Werb

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.

10.1080/2162402x.2015.1008871

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Citations (7)

Proteinase induction by endothelial cells during wound repair.

PubMed (1988)

Banda Mj Herron Gs G F Murphy Zena Werb Dwyer Ks

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Impaired Wound Contraction in Stromelysin-1–Deficient Mice

Annals of Surgery (1999)

Kelli M. Bullard Leif R. Lund John S. Mudgett T.N. Mellin Thomas K. Hunt

Objective To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice. Summary Background Data After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds. Methods Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1–deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for α-smooth muscle actin and fluorescent staining for fibrillar actin. Results Independent of the age of the animal, excisional wounds in stromelysin-1–deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1–deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts. Conclusions Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.

Granulation tissue

Type I collagen

10.1097/00000658-199908000-00017

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Citations (232)