Our Science – Wakefield Website

Lalage M. Wakefield, D.Phil.

Laboratory of Cancer Biology and Genetics Head, Cancer Biology of TGF-beta Section Senior Investigator National Cancer Institute Building 37, Room 4032A 37 Convent Drive, MSC 4255 Bethesda, MD 20892-4255 Phone:   301-496-8351 Fax:   301-496-8709 E-Mail:   wakefiel@dce41.nci.nih.gov

Biography

Dr. Wakefield obtained her D.Phil. in Biochemistry at the University of Oxford, England, for studies on the bioenergetics of the chromaffin granule. In 1983, she joined the Laboratory of Chemoprevention (subsequently the Laboratory of Cell Regulation and Carcinogenesis) at the NCI to work on TGF-betas and their relation to carcinogenesis. Dr. Wakefield was tenured in 1989, and now heads the Cancer Biology of TGF-beta Section in the Laboratory of Cancer Biology and Genetics. In 2001 she received the NCI Outstanding Mentor Award.

Research

Tumor Suppressor and Pro-oncogenic Activities of Transforming Growth Factor-betas in Breast Cancer.

Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that play complex roles in carcinogenesis. The prevailing hypothesis is that TGF-betas have tumor suppressor activity early in the carcinogenic process, but that in the later stages, tumor suppressor activity is lost and pro-oncogenic activities dominate. This switch is thought to be accompanied by a decrease in responsiveness of the tumor cell to TGF-beta, and an increase in TGF-beta ligand secretion that promotes the formation of a permissive stromal environment. Our research program uses genetically-engineered mouse and xenograft model systems to probe this dual role of TGF-betas in breast cancer, and elucidate underlying biological and molecular mechanisms. Where possible, we exploit this knowledge to develop new preventive or therapeutic modalities that target the TGF-beta signaling network. Currently our program consists of three parts, as detailed below.

Probing the dual role of TGF-beta in breast cancer. We have formally tested the hypothesis that TGF-beta can switch from tumor suppressor to prometastatic factor during the course of carcinogenic progression within a given cell lineage. To do this, we have used a xenograft model system of breast cancer progression, based on the MCF10A human breast epithelial line and transformed derivatives. By transducing these cells with a dominant negative form of the TGF-beta receptor and testing for tumorigenicity in nude mice, we have determined the dominant role played by the endogenous TGF-beta system at the various different stages. We have shown that decreased TGF-beta responsiveness alone cannot initiate tumorigenesis, but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic line more aggressively tumorigenic. However, in a high-grade tumorigenic cell line, reduced TGF-beta responsiveness has no effect on primary tumorigenesis, but significantly reduces metastatic efficiency. Our results demonstrate a causal role for loss of TGF-beta response in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but non-metastatic disease, and suggest that at that point TGF-beta switches from tumor suppressor to pro-metastatic factor. We are currently probing the model system for underlying molecular and biological mechanisms, with a particular emphasis on understanding the change in molecular and cellular context that brings about the “metastatic switch�. Our recent work sugests a role for TGF-beta in regulating cancer stem cell dynamics.

TGF-beta antagonists for the suppression of metastasis. Advanced human tumors characteristically show elevated TGF-beta expression, which correlates with poor prognosis. We are developing strategies for the selective neutralization of the pro-metastatic effect of TGF-beta without compromising effects on normal homeostasis and tumor suppression. For “proof of principle�, we generated a transgenic mouse overexpressing a soluble TGF-beta antagonist; this antagonist is a protein in which the soluble extracellular domain of the TGF-beta receptor has been fused to an immunoglobulin Fc domain. Using this mouse model, we have demonstrated that prolonged exposure to this TGF-beta antagonist protects mice against metastasis both in transgenic model of metastatic breast cancer and in a tail vein injection model of metastatic melanoma. Surprisingly, the anticipated side-effects of immune system dysfunction and increased spontaneous carcinogenesis were not observed, suggesting that this approach has clinical potential for the prevention of metastatic progression. Future directions with this project include (i) analysis of basis of selectivity of the antagonist for the deleterious, pro-metastatic TGF-beta, (ii) identification of the steps in the metastasic process that are affected, (iii) development of improved antagonists and (iv) determination of molecular properties that may predict response of a metastatic tumor to anti-TGF-beta therapy.

Signal transduction pathways underlying tumor suppressor and pro-oncogenic activities of TGF-betas in the breast. Signal transduction from the TGF-betas is mediated by multiple pathways, including the Smad, MAPK, PI3K/Akt and pp2A/p70s6K pathways. We have previously hypothesized that the tumor suppressor and pro-oncogenic effects of TGF-betas may be mediated by different signal transduction pathways. If this were true, the development of targeted therapeutics with desirable side-effect profiles would be greatly facilitated. To begin to address this question, we have chosen to concentrate initially on the Smad pathway. Three receptor-activated Smads, Smads1, 2 and 3 are activated by the TGF-beta receptor in breast-derived cell lines. Using Smad null or conditional null mice, and mammary epithelial cells derived from these, we are systematically testing the Smad dependency of the various different biological responses to TGF-beta, and the role of the Smads in tumorigenic progression. We hope to be able to determine the relative importance of Smad vs. non-Smad pathways, and the balance between these, in determining the biological outcome of TGF-beta signaling.

Our collaborators include Miriam Anver, SAIC-Frederick; Erwin Bottinger, Albert-Einstein College of Medicine, NY; Mary Helen Barcellos-Hoff, Lawrence Berkeley Lab, CA; Fred Miller, Karmanos Cancer Institute, MI; Scott Lonning, Jan Pinkas, Genzyme Corp.; Jay Berzofsky, Chuxia Deng, Kent Hunter, NIH.

This page was last updated on 6/12/2008.