Dynamics of the Cellular Microenvironment in Development and Neoplasia
Our laboratory investigates problems in the fields of development, proteolysis, inflammation and cancer. We exploit the lessons of using mechanisms arising out of the studies in development to understand diseases such as asthma and cancer. We are interested in how matrix metalloproteinases (MMPs) mediate remodeling of the extracellular matrix (ECM), thus regulating cell behavior. We have learned that the ECM is not inert and only structural in nature. The stromal microenvironment, specifically ECM, carries information through the interaction with adhesion receptors and is a signaling unit. Its remodeling by proteases is a central switch in altering homeostasis (normalcy vs. malignancy, apoptosis, and growth).
We study the development of two tissues that undergo the majority of their morphogenesis in three areas : the postnatal animal, the skeleton, and the mammary gland. They require extensive tissue remodeling, unlike embryonic development. Our studies on how bone recruits a vascular system during endochondral ossification has led to new experiments on the regulation of angiogenesis during tumor progression. Our studies on branching morphogenesis and maintenance of the differentiated state of epithelial during mammary development has opened up new approaches to the regulation of metastasis during breast cancer progression.
In the area of breast cancer, our studies are focusing on the mechanisms underlying metastasis. We have found that the stromal microenvironment is critical in regulating cell behavior. Indeed, ECM remodeling by proteases can lead to the development of mammary tumours, recritment of innate immune cells and the activation of angiogenic growth factors. As mutated epithelial cells progress towards malignancy, they sustain a progressive loss of growth control, striking alterations in tissue structure and acquire genomic instability, which eventually give rise to tumours. We are investigating the tissue-specific transcription factors that allow these neoplastic cells to manipulate the signaling at their cell surface by proteolysis, re-organize their cytoarchitecture, and become invasive and malignant. At the same time they orchestrate the recruitment of innate immune cells such as macrophages and of new blood vessels. We are using novel live cell and intravital microscopy methods for visualizing the behavior and interactions of nomal epithelium, tumor cells, immune cells and vascular cells and sites of bacterial infection in real-time at the cellular level in living animals. These studies are changing the way that we view cancer. Our studies are beginning to provide compelling evidence that innate infllammatory cells, including mast cells, macrophages and neutrophils contribute to tumorigenesis, and are laying the groundwork for potential intervention in inflammation in cancer.
We are also investigating the role of stem and progenitor cells during development and as an origin of breast cancer. Proteases and ECM remodeling play roles in controling the nature of the stem cell niche. Using new methods that allow us to transduce mammary stem cells, then study them in culture or transplant them back orthotopically we are beginning to elucidate the controlling mechanisms for mammary gland development and neoplasia. These studies promise to provide a molecular mechanistic framework for understanding tissue morphogenesis and remodelling.
Sternlicht, M. D., A. Lochter, C. J. Sympson, B. Huey, J.-P. Rougier, J. W. Gray, D. Pinkel, M. J. Bissell & Z. Werb (1999). The stromal proteinase MMP-3/stromelysin-1 promotes mammary carcinogenesis. Cell. 98: 137-146.
Coussens, L. M. & Z. Werb (2002). Inflammation and cancer. Nature 420:860-867.
Egeblad, M. & Z. Werb (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2: 163-176.
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
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.
Page-McCaw, A., A. J. Ewald & Z. Werb (2006). Matrix metalloproteinases and the genetic regulation of tissue remodeling. 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.
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.
Kouros-Mehr, H., S. K. Bechis, E.M. Slorach, L. E. Littlepage, M. Egeblad, A. J. Ewald, S.-Y. Pai, I-C. Ho & Z. Werb (2008). GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 13:141-152.
Du, R., K. Lu, C. Petritsch, P. Liu, R. Ganss, E. Passague, H. Song, S. VandenBerg, R.S. Johnson, Z. Werb & G. Bergers (2008). HIF1a 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.
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.
Egeblad, M., A. J. Ewald, H. A. Askautrud, B. E. Welm, M. Truitt, E. Bainbridge, G. Peeters, M. Krummell & Z. Werb (2008). Imaging stromal cell behavior in intact tumor microenvironments. Disease Models Mech. 1:155-167.
Lu, P., A. J. Ewald, G. R. Martin & Z. Werb (2008). Genetic mosaic analysis reveals FGF receptor 2 is required in terminal end buds during mammary gland branching morphogenesis. Dev. Biol. 231:77-87.
Lu, P. & Z. Werb (2008). Patterning mechanisms of branched organs. Science. In press.