Zena Werb, PhD

Professor & Vice Chair
Department of Anatomy
+1 415 476-4622

The Werb laboratory uses genetics, cell and molecular biology and functional genomics in mouse models and patient materials to determine mechanisms controlling stem cell fate decisions, cell migration and invasion, inflammation and angiogenesis during mammary gland development and breast tumorigenesis. We are particularly concentrating on how the interactions of the cellular microenvironment with the normal  epithelial cells or cancer cells enhance or suppress growth, development or metastasis.

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. Our laboratory uses genetics, cell and molecular biology and functional genomics in mouse models and patient materials to determine mechanisms controlling cell fate decisions, cell survival, cell migration and invasion, inflammation and angiogenesis during development and tumorigenesis.

By genetic and molecular approaches we are learning how signaling are involved in the process of branching morphogenesis in the mammary gland and how these are co-opted during tumor progression. One class of molecules that is giving insights into these developmental mechanisms is the matrix metalloproteinase (MMP) family. These enzymes play a critical role by regulating ECM and cell surface proteins, growth and angiogenic factors, cell recruitment, cell proliferation and apoptosis. Both cleavage of the target proteins that initiates rapid and irreversible signal transduction events and non-proteolytic functions of the MMPs lead to altered cell behavior. The consequences of these signals are morphogenesis, cell migration, physiologic tissue remodeling or pathologic processes.

Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, while the adaptive immune system participates in mammary gland postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement and luminal lineage differentiation. This function of adaptive immune responses regulating normal development changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance during cancer transformation. We are using single cell methods to characterize the immune cells, particularly the myeloid cells, present in tumors and their metastases to learn how these cells may enhance or suppress tumor progression. We are seeking new targets for therapy.

We are studying the role of stem and progenitor cells during development and as an origin of cancer and cancer metastasis. The stem cell niche is a key factor in regulating the transfer of stem cells from the quiescent niche to the proliferative niche in developing mammary gland and breast cancer. Prevailing theories hypothesize that metastases are seeded by rare tumor cells, which function like stem cells in their ability to initiate and propagate metastases. We are using single cell methods such as RNA-seq to characterize the heterogeneity of metastasis-initiating cells and to isolate them from patient-derived xenograft (PDX) models of breast cancer, thereby to investigate mechanisms of metastatic disease and its therapeutic control.

Primary Thematic Area: 
Developmental & Stem Cell Biology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Determining mechanisms controlling stem cell fate decisions, cell migration and invasion, inflammation and angiogenesis during mammary gland development and breast tumorigenesis.

Websites

Featured Publications: 

A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway.

Cell stem cell

Kessenbrock K, Dijkgraaf GJ, Lawson DA, Littlepage LE, Shahi P, Pieper U, Werb Z

GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression.

Nature cell biology

Chou J, Lin JH, Brenot A, Kim JW, Provot S, Werb Z

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils.

Proceedings of the National Academy of Sciences of the United States of America

Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, Passegué E, Werb Z

Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.

Nature

Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, Yaswen P, Goga A, Werb Z

Adaptive Immune Regulation of Mammary Postnatal Organogenesis.

Developmental cell

Plaks V, Boldajipour B, Linnemann JR, Nguyen NH, Kersten K, Wolf Y, Casbon AJ, Kong N, van den Bijgaart RJ, Sheppard D, Melton AC, Krummel MF, Werb Z