Lalage M. Wakefield, D.Phil.
Lalage M. Wakefield, D.Phil.
Senior Investigator
Head, Cancer Biology of TGF-beta Section

Dr. Wakefield is a leading investigator in the complex cancer biology of the TGF-beta pathway, with a particular focus on breast cancer. Her preclinical studies contributed to the development of anti-TGF-beta therapeutics in oncology, some of which have advanced to early clinical trials. Her current research program uses innovative imaging, genomic and animal modeling methods to address the role of TGF-betas in regulating cancer stem cells, elucidate mechanisms underlying the dual role of TGF-beta in cancer, and develop and exploit preclinical models to support the clinical development of TGF-beta antagonists.

Areas of Expertise
1) TGF-beta, 2) breast cancer, 3) metastasis, 4) mouse models, 5) targeted therapy, 6) cancer stem cells

Contact Info

Lalage M. Wakefield, D.Phil.

Center for Cancer Research
National Cancer Institute

Building 37, Room 4032A
Bethesda, MD 20892-4255
301-496-8351

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 the development of many different tumor types. 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 come to dominate. Both facets of TGF-beta biology involve the tumor stroma as well as the tumor parenchyma, and affect multiple biological processes. TGF-beta pathway antagonists are now in early phase clinical trials with the goal of blocking the pro-oncogenic effects of TGF-beta, so understanding the dual role of TGF-beta will be critical to the safe and effective development of these agents.

Our research program uses a variety of approaches in preclinical mouse model systems to address the role of TGF-betas in breast cancer, and to elucidate underlying mechanisms. Where possible, we apply this knowledge to further the development of therapeutic strategies that target the TGF-beta pathway.

Probing the dual role of TGF-beta in breast cancer. 
Our major goal in this part of the program is to elucidate biological and molecular mechanisms underlying the dual role of TGF-beta. Here we are specifically focused on the effects of TGF-beta on the tumor parenchyma, and much of our current work uses a powerful xenograft model system of breast cancer progression, based on the MCF10A human breast epithelial line and its transformed derivatives. This model exemplifies the dual role of TGF-beta in that the premalignant and early malignant lines show tumor suppressor responses to TGF-beta while the most aggressively malignant line responds to TGF-beta with enhanced metastasis.

We are applying integrated genomic approaches to this model to identify major changes in molecular context that influence the output of the TGF-beta signal. Key findings are then replicated in primary human breast cancer cell cultures.

One goal is to develop TGF-beta-related gene signatures that can identify which aspect of TGF-beta dominates in a given tumor. Importantly, we have identified a role for TGF-beta in regulating the cancer stem cell population, and we have developed a novel fluorescent stem cell reporter which allows us to visualize the cancer stem cell in its native habitat with contextual cues intact. Understanding how TGF-beta modulates cancer stem cell dynamics should give new insights into how to target this therapy-resistant tumor cell subpopulation.

TGF-beta antagonists for the suppression of metastasis. 
Advanced human tumors characteristically show elevated TGF-beta expression, which correlates with poor prognosis. We and others have previously shown that antagonizing TGF-beta therapeutically can suppress tumor metastasis without the expected deleterious effects on normal homeostasis and early tumorigenesis. As a result, anti-TGF-beta therapeutics are now in Phase I or II clinical oncology trials.

Our goal in this part of the program is to use preclinical models to elucidate underlying mechanisms and support the clinical development of these agents. Mechanistically we have shown that the therapeutic efficacy of anti-TGF-beta antibodies involves multiple small effects on many different cellular compartments (the Death by a Thousand Cuts model) that aggregately result in the generation of a more hostile tumor microenvironment. We have assembled a large panel of transplantable mouse models of metastatic breast cancer and demonstrated heterogeneous responses to TGF-beta antagonism across the panel.

Future directions with this project include

  1. Mechanisms underlying adverse responses to TGF-beta antagonism
  2. Development of predictive biomarkers for patient selection, and
  3. Improving therapeutic efficacy through rational combinations with other therapeutics.

Collaborators.  Our collaborators include Dominic Esposito, ATP, FNLCR; Miriam Anver, SAIC-Frederick; Stephen Hewitt, NCI-ATC; Jay Berzofsky, Kent Hunter, Maxwell Lee and Howard Yang, NCI; Rea Ravin, NICHD; William Smith, Suburban Hospital.

Scientific Focus Areas:
Cancer Biology, Cell Biology, Molecular Biology and Biochemistry, Stem Cell Biology
  1. 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.
    J. Clin. Invest. 109: 1607-15, 2002. [ Journal Article ]
  2. Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM.
    J. Clin. Invest. 112: 1116-24, 2003. [ Journal Article ]
  3. 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.
    Cancer Res. 68: 3835-43, 2008. [ Journal Article ]
  4. Sato M, Kadota M, Tang B, Shan M, Weng J, Welsh MA, Flanders KC, Michalowski AM, Yang HH, Clifford RJ, Lee M, and Wakefield LM.
    Breast Cancer Res. 16: R57, 2014. [ Journal Article ]
  5. Tang B, Raviv A, Esposito D, Daniel C, Nghiem B-T, Garfield S, Lim L, Mannan P, Robles AI, Smith WI, Zimmerberg J, Ravin R, and Wakefield LM.
    Stem Cell Reports. 4: 155-169, 2015. [ Journal Article ]

Dr. Wakefield obtained her BA and D.Phil. degrees in Biochemistry at the University of Oxford, England. In 1983, she joined the Laboratory of Chemoprevention at the NCI to work with Drs. Michael Sporn and Anita Roberts on the newly-discovered TGF-beta proteins 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. She received the NCI Outstanding Mentor Award in its inaugural year.

Name Position
Kathleen C. Flanders, Ph.D. Staff Scientist
Nellie Moshkovich Postdoctoral Fellow (CRTA)
Binwu Tang, Ph.D. Staff Scientist
Yuan Yang M.D., Ph.D. Research Biologist

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 the development of many different tumor types. 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 come to dominate. Both facets of TGF-beta biology involve the tumor stroma as well as the tumor parenchyma, and affect multiple biological processes. TGF-beta pathway antagonists are now in early phase clinical trials with the goal of blocking the pro-oncogenic effects of TGF-beta, so understanding the dual role of TGF-beta will be critical to the safe and effective development of these agents.

Our research program uses a variety of approaches in preclinical mouse model systems to address the role of TGF-betas in breast cancer, and to elucidate underlying mechanisms. Where possible, we apply this knowledge to further the development of therapeutic strategies that target the TGF-beta pathway.

Probing the dual role of TGF-beta in breast cancer. 
Our major goal in this part of the program is to elucidate biological and molecular mechanisms underlying the dual role of TGF-beta. Here we are specifically focused on the effects of TGF-beta on the tumor parenchyma, and much of our current work uses a powerful xenograft model system of breast cancer progression, based on the MCF10A human breast epithelial line and its transformed derivatives. This model exemplifies the dual role of TGF-beta in that the premalignant and early malignant lines show tumor suppressor responses to TGF-beta while the most aggressively malignant line responds to TGF-beta with enhanced metastasis.

We are applying integrated genomic approaches to this model to identify major changes in molecular context that influence the output of the TGF-beta signal. Key findings are then replicated in primary human breast cancer cell cultures.

One goal is to develop TGF-beta-related gene signatures that can identify which aspect of TGF-beta dominates in a given tumor. Importantly, we have identified a role for TGF-beta in regulating the cancer stem cell population, and we have developed a novel fluorescent stem cell reporter which allows us to visualize the cancer stem cell in its native habitat with contextual cues intact. Understanding how TGF-beta modulates cancer stem cell dynamics should give new insights into how to target this therapy-resistant tumor cell subpopulation.

TGF-beta antagonists for the suppression of metastasis. 
Advanced human tumors characteristically show elevated TGF-beta expression, which correlates with poor prognosis. We and others have previously shown that antagonizing TGF-beta therapeutically can suppress tumor metastasis without the expected deleterious effects on normal homeostasis and early tumorigenesis. As a result, anti-TGF-beta therapeutics are now in Phase I or II clinical oncology trials.

Our goal in this part of the program is to use preclinical models to elucidate underlying mechanisms and support the clinical development of these agents. Mechanistically we have shown that the therapeutic efficacy of anti-TGF-beta antibodies involves multiple small effects on many different cellular compartments (the Death by a Thousand Cuts model) that aggregately result in the generation of a more hostile tumor microenvironment. We have assembled a large panel of transplantable mouse models of metastatic breast cancer and demonstrated heterogeneous responses to TGF-beta antagonism across the panel.

Future directions with this project include

  1. Mechanisms underlying adverse responses to TGF-beta antagonism
  2. Development of predictive biomarkers for patient selection, and
  3. Improving therapeutic efficacy through rational combinations with other therapeutics.

Collaborators.  Our collaborators include Dominic Esposito, ATP, FNLCR; Miriam Anver, SAIC-Frederick; Stephen Hewitt, NCI-ATC; Jay Berzofsky, Kent Hunter, Maxwell Lee and Howard Yang, NCI; Rea Ravin, NICHD; William Smith, Suburban Hospital.

Scientific Focus Areas:
Cancer Biology, Cell Biology, Molecular Biology and Biochemistry, Stem Cell Biology

Publications

  1. 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.
    J. Clin. Invest. 109: 1607-15, 2002. [ Journal Article ]
  2. Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM.
    J. Clin. Invest. 112: 1116-24, 2003. [ Journal Article ]
  3. 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.
    Cancer Res. 68: 3835-43, 2008. [ Journal Article ]
  4. Sato M, Kadota M, Tang B, Shan M, Weng J, Welsh MA, Flanders KC, Michalowski AM, Yang HH, Clifford RJ, Lee M, and Wakefield LM.
    Breast Cancer Res. 16: R57, 2014. [ Journal Article ]
  5. Tang B, Raviv A, Esposito D, Daniel C, Nghiem B-T, Garfield S, Lim L, Mannan P, Robles AI, Smith WI, Zimmerberg J, Ravin R, and Wakefield LM.
    Stem Cell Reports. 4: 155-169, 2015. [ Journal Article ]

Biography

Dr. Wakefield obtained her BA and D.Phil. degrees in Biochemistry at the University of Oxford, England. In 1983, she joined the Laboratory of Chemoprevention at the NCI to work with Drs. Michael Sporn and Anita Roberts on the newly-discovered TGF-beta proteins 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. She received the NCI Outstanding Mentor Award in its inaugural year.

Team

Name Position
Kathleen C. Flanders, Ph.D. Staff Scientist
Nellie Moshkovich Postdoctoral Fellow (CRTA)
Binwu Tang, Ph.D. Staff Scientist
Yuan Yang M.D., Ph.D. Research Biologist