Lalage M. Wakefield, D.Phil.
Laboratory of Cancer Biology and Genetics
Building 37, Room 4032A
Bethesda, MD 20892-4255
Transforming Growth Factor-βs and Cancer Stem Cells in Breast Cancer Progression
Transforming growth factor-βs (TGF-βs) play central roles in adult homeostasis and response to injury. Consequently, dysregulation of this pathway is associated with many disease states, including cancer. In epithelial cancers the prevailing hypothesis is that TGF-βs have tumor suppressor activity early in the carcinogenic process, but that in the later stages, tumor suppressor activity is lost and pro-oncogenic activities come to dominate. TGF-β pathway antagonists are in early phase clinical oncology trials, so understanding the complex dual role of TGF-β will be critical to the safe and effective development of these agents. Our two-part research program applies a multifaceted approach to address this problem.
Probing the dual role of TGF-β in breast cancer The major goal of this part of the program is to understand the positive and negative effects of TGF-β that are targeted towards the cancer cell itself, and how these change with disease progression. Currently we have a strong focus on the cancer stem cell subpopulation, which is responsible for initiating and sustaining the tumor, and driving cancer recurrence when therapeutic approaches fail. We work with xenograft and genetically engineered mouse models of breast cancer progression, and we apply integrated genomic, biologic and imaging approaches to identify the effects of TGF-β on the cancer stem cells and their more differentiated offspring. One mechanistic goal is to identify key components that influence the net output of the TGF-β signal (tumor suppressive vs tumor promoting). An important recent advance is our development of a novel fluorescent stem cell reporter which allows us to visualize the cancer stem cell in its native habitat, with all the contextual cues intact. We now have the tools to build a dynamic picture of cancer stem cell fate and phenotypic plasticity in real-time through functional imaging in vivo and in 3D models in vitro. Understanding how TGF-β modulates cancer stem cell dynamics during breast cancer progression should give new insights into how to target this therapy-resistant tumor cell subpopulation.
Targeting the TGF-β pathway to suppress metastasis Many advanced human tumors show elevated TGF-β expression, which correlates with poor prognosis. We and others previously made the surprising finding that antagonizing TGF-β in mouse models could suppress metastasis without the expected deleterious effects on normal homeostasis and early tumorigenesis. As a result, anti-TGF-β therapeutics are now in early phase clinical oncology trials. In this part of the program we use mouse models of metastatic breast cancer to elucidate mechanisms and support the clinical development of these agents. We have previously shown that the therapeutic efficacy of anti-β-beta antibodies involves multiple small effects on many different cellular compartments (“death by a thousand cuts”), with most of the efficacy dependent on reactivation or unmasking of effective anti-tumor immunity. Using an expanded panel of models, we find heterogeneous responses to TGF-β antagonists, with a minority of models showing undesirable adverse responses. Work is ongoing to investigate mechanisms and develop predictive biomarkers for patient selection, as well as to improve efficacy through rational combinations with other therapeutics.
Our collaborators include John Condeelis, Albert Einstein College of Medicine; Caroline Hill, Cancer Research UK; Sushil Rane, NIDDK; Maxwell Lee, NCI; Kent Hunter, NCI
Scientific focus areas:
Cancer Biology, Cell Biology, Molecular Biology and Biochemistry, Stem Cell Biology
Sato M, Kadota M, Tang B, Yang HH, Yang YA, Shan M, Weng J, Welsh MA, Flanders KC, Nagano Y, Michalowski AM, Clifford RJ, Lee MP, Wakefield LM. An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer. Breast Cancer Res. 2014;16(3):R57.
Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C, Kohn E, Tang B, Sabzevari H, Anver MR, Lawrence S, Danielpour D, Lonning S, Berzofsky JA, Wakefield LM. An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 2008;68(10):3835-43.
Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest. 2003;112(7):1116-24.
Tang B, Raviv A, Esposito D, Flanders KC, Daniel C, Nghiem BT, Garfield S, Lim L, Mannan P, Robles AI, Smith WI Jr, Zimmerberg J, Ravin R, Wakefield LM. A flexible reporter system for direct observation and isolation of cancer stem cells. Stem Cell Reports. 2015;4(1):155-69.
Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G, Wakefield LM. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest. 2002;109(12):1607-15.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on June 15th, 2017