Zena Werb, Ph.D.

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.