Biomedical Sciences Graduate Program | University of California, San Francisco

Zena Werb, PhD
Functions of the Extracellular Microenvironment in Development and Cancer

Selected Publications | Complete Publications

phone	(415) 476-4622
email	zena.werb@ucsf.edu
additional websites	Lab Website Cancer Center Tetrad Graduate Progam
secondary research affiliation	Cancer Biology & Cell Signaling

Cell-cell and cell-extracellular matrix (ECM) interactions provide cells with information essential for controlling morphogenesis, cell-specific fate determination, gain or loss of tissue-specific functions, cell migrations, tissue repair and cell death. The remodeling of the extracellular matrix regulates normal cell behavior and the tumor microenvironment. There is a fundamental link between cellular morphogenesis, ECM and the regulation of gene expression. Our laboratory uses genetics, cell and molecular biology and functional genomic approaches in concert with real-time, confocal imaging approaches to determine mechanisms controlling cell fate decisions, cell survival, cell migration and invasion, vasculogenesis, inflammation and angiogenesis during development and tumorigenesis.

We are studying several critical developmental processes: endochondral bone formation, adipogenesis and branching morphogenesis in the mammary gland. By genetic and molecular approaches we are learning how EGF, VEGF, wnt and FGF receptor signaling are involved in these developmental processes. One class of molecules that is giving insights into these developmental mechanisms is the matrix metalloproteinase family. These enzymes play a critical role by regulating extracellular matrix and cell surface proteins, growth and angiogenic factors, cell recruitment, cell proliferation and apoptosis. Cleavage of the target proteins initiates rapid and irreversible signal transduction events that lead to altered cell behavior. We wish to determine the molecular and cellular targets of the proteinases, and how these regulate the signaling pathways. The consequences of these signals are morphogenesis, cell migration, physiologic tissue remodeling or pathologic processes.

We are also studying the role of stem and progenitor cells during development and as an origin of cancer. Our studies have relevance to the nature of the stem cell niche because proteinases are key factors in regulating the transfer of stem cells from the quiescent niche to the proliferative niche for hematopoietic stem cells, endothelial progenitors and bone mesenchymal precursors as well as in developing mammary gland and breast cancer.

We are using the lessons from development to elucidate the events in breast cancer. We are using molecular and in vivo imaging approaches to elucidate genes regulating neoplastic initiation, progression, inflammatory response, angiogenesis malignant conversion and metastasis. Is the inflammatory response to tumors involved in enhancing or suppressing tumor progression? What is the transcriptional basis of progression to metastasis? We are using in vivo imaging to follow the behavior of cells in tumors as a first step to understanding their functions. The tumor microenvironment is modified during tumor progression. Why is the extracellular matrix altered during tumor progression? We are studying how proteinases and related enzymes and the bioactive molecules that they liberate regulate the cellular microenvironment and what role they play in tumor progression.

Selected Publications

Coussens, L.M. & Z. Werb (2002). Inflammation and cancer. Nature 420:860-867.

Egeblad, M. & Z. Werb (2002). New roles for the matrix metalloproteinases in the progression of cancer. Nature Rev. Cancer. 2: 163-176.

Affolter, M., S. Bellusci, N. Itoh, B. Shilo, J.-P. Thiery & Z. Werb (2003). Tube or not tube: remodeling epithelial tissues by branching morphogenesis. Dev. Cell.4: 11-18.

Li, Y., B. Welm, K. P., S. Huang, M. Chamorro, T. Rowlands, P. Cowin, M. Egeblad, Z. Werb, L. K. Tan, J. Rosen & H. E. Varmus (2003). Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl. Acad. Sci. USA. 100: 15853-1585.

Wiseman, B.S., M. D. Sternlicht, L. R. Lund, C. M. Alexander, J. Mott, M. J. Bissell, P. Soloway, S. Itohara & Z. Werb (2003). Site-specific positive and negative activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J. Cell Biol. 162: 1123-1133.

Stickens, D., D. J. Behonick, N. Ortega, B. Heyer, B. Hartenstein, Y. Yu, M. Schorpp-Kistner, A. Fosang, P. Angel & Z. Werb (2004). Altered endochondral bone formation in matrix metalloproteinase-13 deficient mice. Development. 131: 5883-5895.

Littlepage, L.E., M. Egeblad & Z. Werb (2005). Coevolution of cancer and stromal cellular responses. Cancer Cell. 7:499-500.

Ortega, N., D. J. Behonick, C. Colnot, D. H. Cooper & Z. Werb (2005). Galectin-3 is a downstream regulator of MMP-9 function during endochondral bone formation. Mol. Biol. Cell. 16: 3028-3039.

Radisky, D. C., D. D. Levy, L. E. Littlepage, H. Liu, C. M. Nelson, J. E. Fata, D. Leake, E. L. Godden, D. G. Albertson, M.A. Nieto, Z. Werb & M. J. Bissell. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 436:123-127.

Sternlicht, M.D., S.W. Sunnarborg, H. Kouros-Mehr, Y. Yu, D. C. Lee & Z. Werb (2005). Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development. 132:3923-3933.

Stickens, D., B. M. Zak, N. Rougier, J. D. Esko & Z. Werb (2005). Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development. 132:5055-5068.

Kouros-Mehr, H. & Z. Werb (2006). Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev. Dyn. 235:3404-3412.

Kouros-Mehr, H., E. M. Slorach, M. D. Sternlicht & Z. Werb (2006). GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 127:1041-1055

Liu, Z., X. Zhou, L. A. Diaz, R. M. Senior & Z. Werb (2005). Synergy between a plasminogen cascade and MMP-9 in autoimmune disease. J. Clin. Invest. 115: 879-887.

Sternlicht, M. D., A. M. Dunning, D. H. Moore, P. D. P. Pharoah, D. G. Ginzinger, K. Chin, J. W. Gray, F. M. Waldman, B. A. J. Ponder & Z. Werb (2006). Prognostic value of PAI1 in invasive breast cancer: evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression. Canc. Epidemiol. Biomarkers. Prev. 15: 2107-2114.

Fata, J.E., H. Mori, A. J. Ewald, H. Zhang, E. Yao, Z. Werb & M. J. Bissell (2007). The MAPK ERK-1,2 pathway integrates distinct and antagonistic signals from TGF a and FGF7 in morphogenesis of mouse mammary epithelium. Dev. Biol. [ Epub 16 March 2007 ].

Lum, D.H., J. Tan, S. D. Rosen & Z. Werb (2007). Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase, Sulf2. Mol. Cell. Biol. 27:678-688.

Page-McCaw, A., A. J. Ewald & Z. Werb (2007). Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. Nat. Rev. Mol. Cell Biol. 8: 221-233.

Sneddon, J.B. & Z. Werb (2007). Location, location, location: The cancer stem cell niche. Cell Stem Cell. 1: 607-611. PMID: 18371402

Yu, W., X. Fang, et al. (2007). Formation of cysts by alveolar type II cells in three-dimensional culture reveals a novel mechanism for epithelial morphogenesis. Mol. Biol. Cell. 18: 1693-1700. PMID: 17332496.

Adler, A.S., L. E. Littlepage et al. (2008). Essential role of CSN5 isopeptidase activity in breast cancer progression. Cancer Res. 68: 506-515. PMID: 18199546

Du, R., K. Lu, et al. (2008). HIF1 a promotes tumor progression by inducing the recruitment of bone marrow-derived vascular modulatory cells to regulate angiogenesis and tumor invasion. Cancer Cell. 13:206-220. PMID: 18328425

Ewald, A.J., A. Brenot, M. Duong, B.S. Chan & Z. Werb (2008). Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell. 14:570-581.

Kouros-Mehr, H., S. K. Bechis, et al. (2008). GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 13:141-52. PMID: 18242514.

Kouros-Mehr, H., J.-W. Kim, S. K. Bechis & Z. Werb (2008). GATA-3 and the regulation of the mammary luminal cell fate. Curr. Opin. Cell Biol. 20:164-170. PMID: 18358709.

Lu, P., Y. Yu, Y. Perdue & Z. Werb (2008). The apical ectodermal ridge is a timer for generating distal limb progenitors. Development. 135:1395-405.PMID: 18359901.

Martín-Belmonte, F., W. Yu, et al. (2008). Cell polarity dynamics controls the mechanism of lumen formation in epithelial morphogenesis. Curr. Biol. 18:507-513. PMID: 18394894.

Welm, B.E, G. J. P. Dijkgraaf, A. S. Bledau, A. L. Welm & Z. Werb (2008). Lentiviral transduction of stem cells for genetic analysis of mammary development and breast cancer. Cell Stem Cell. 2:90-102. PMID: 18371425.

Kessenbrock, K., M. Krumbholz, et al. (2009). Netting neutrophils in autoimmune small vessel vasculitis. Nature Med. 15: 623-625.

Lilla, J. N., R. Joshi, C. S. Craik & Z. Werb (2009). Active plasma kallikrein localizes to mast cells and regulates epithelial cell apoptosis, adipocyte differentiation and stromal remodeling during mammary gland involution. J. Biol. Chem. 84:13792-13803.

information last updated August 2009