Source: Interfolio F180
Brunie Felding
Research Focus
Mechanisms and inhibition of tumor metastasis.
Our goal is to define and target molecular mechanisms that control tumor metastasis. Metastasis is the main cause of death in cancer patients. If dissemination of tumor cells from primary to distant sites could be prevented or blocked after it has occurred, the mortality of patients with solid tumors could be drastically reduced, and cancer would be curable disease.
To develop effective approaches for prevention and inhibition of metastatic disease, we address four major questions:
1) Which cells are responsible for metastatic dissemination?
2) Which are key genes and functional properties that promote tumor metastasis?
3) How can we target metastatic tumor cells and inhibit functions that are essential for cancer spreading?
4) How do tumor cell metabolism and the host microenvironment control cancer development and dissemination?
We hypothesize that genetic alterations and aberrant tumor cell metabolism determine metastatic activity and cancer progression. Focusing primarily on breast cancer, we found that a subset of aggressive cancer cells within a primary tumor express constitutively activated adhesion receptors that promote tumor cell dissemination. These activated adhesion receptors can serve as targets for identification and inhibition of metastatic tumor cells. Following one of the most deadly forms of breast cancer metastasis, we found that brain metastatic breast cancer cells adapt to the microenvironment of the brain by metabolic alterations that foster growth within the brain tissue. Dissecting the earliest steps of breast cancer colonization of the brain, we were able to define sequential events that are critical for tumor cell survival and penetration of the blood brain barrier. These mechanisms involve adhesive functions, interaction with vascular cells, and coagulation activity that could be targeted for prevention of brain metastatic disease.
Following the challenge to develop break-though ideas that could lead to tangible reduction in breast cancer mortality, we focused on tumor cell metabolism and demonstrated that mitochondrial complex I activity controls aggressiveness in breast cancer. Our finding show that regulation of the tumor cell NAD+/NADH redox balance through complex I affects breast cancer growth and metastasis. The results translated into a new therapeutic approach based on treatment with NAD+ precursors that prevent breast cancer progression. Current standard of care for cancer patients relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. However, evolutionary models predict, and clinical experience indicates, that selective pressure imposed by these approaches causes survival of resistant clones that eventually reactivate the disease. Therapeutic normalization of tumor cell metabolism could be an effective way to interfere with the expansion of residual clones. Thus, combination of standard therapy with the treatment we developed may halt breast cancer progression and prevent recurrence.
Links
Against Metastasis....Strip Away the Secret
TSRI Philanthropy: Scientist Profile: Interfering with the Spread of Breast Cancer and Melanoma
Scientists Find Promising New Approach to Preventing Progression of Breast Cancer
Education
Ph.D. (Biochemistry), Philipps University Marburg, 1984M.S. (Biology), Justus-Liebig University of Giessen, 1980
Professional Experience
2003-Present Associate Professor, Scripps Research1995-2003 Assistant Professor, Scripps Research
1993-1995 Research Associate Sr, Scripps Research
1991-1993 Head of Cell Adhesion Research Group at E. Merck KG, Department of Preclinical Pharmaceutical Research, Darmstadt, Germany
1989-1991 External Principal Investigator, E. Merck KG, Darmstadt, Germany, Visiting Scientist with Dr. D.A. Cheresh at The Scripps Research Institute, Department of Immunology, La Jolla, CA
1987-1989 Research Associate with Dr. S. Hakomori, Fred Hutchinson Cancer Research Center and The Biomembrane Institute, Division of Cellular Immunology, Seattle, WA
1984-1987 Research Associate with Dr. H. Wiegandt, Department of Physiological Chemistry, Philipps University Marburg, Germany
Awards & Professional Activities
Chartered Member on NIH and DOD BCRP Study Sections
1997 – 2000 Member of the Pathobiology PBY-4 Review Panel of the DOD Breast Cancer Research Program
2002 – 2005 Member of the Pathobiology PBY-2 Review Panel of the DOD Breast Cancer Research Program
2004 – 2005 Member of the Cancer Biotherapeutics Development NIH Small Business and Technology Transfer (SBIR/STTR) Study Section
2005 – 2006 Member of the NIH Onc-L (12) B Cancer Diagnostic and Treatment Study Section2004 – 2005 Member of the Committee Western 4B Review Panel of the American Heart Association
2006 – 2011 Member of the NIH/NCI Tumor Progression and Metastasis (TPM) Study Section2020 – 2022 Member of the NIH/NCI Tumor Microenvironment (TME) Study Section2022 - present Member of the NIH/NCI Tumor Host Interaction (THI) Study SectionInvited Ad hoc Reviewer
NIH Study Sections, Special Emphasis Panels, Scientific Review Groups
TPM Tumor Progression and Metastasis
TME Tumor Microenvironment
CDP Chemo and Dietary Prevention
ZRG1 CB-H Intercellular Interactions
S10 Shared Instrument Grants
ZCA1 SRB-1 Omnibus Study Sections
ZCA1 SRB-2 Metabolic Dysregulation and Cancer Risk
ZRG1 CBD Cancer Biotherapeutic Development
ZRG1 CB Cell Biology
Foundations
National Science Foundation
Susan G. Komen Foundation
Arizona Biomedical Research Commission
Cancer Research UK
Italian Foundation for Cancer Research (AIRC)
Swiss National Science Foundation
Dutch Cancer Society
Erwin Schroedinger Science Program Austria
New Zealand Cancer Foundation
Selected Publications
Takada, Yoshikazu; Takada, Yoko K.; Shimoda, Michiko; Maverakis, Emanual M.; Felding, Brunie H.; Cheng, R H. Soluble CD40L activates soluble and cell-surface integrin avß3, a5ß1, and a4ß1 by binding to the allosteric ligand-binding site (site 2).. The Journal of Biological Chemistry 2021, 296, 1 - 11.
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Johnson, Caroline H.; Santidrian, Antonio F.; Leboeuf, Sarah E.; Kurczy, Michael E.; Rattray, Nicholas J.; Rattray, Zahra; Warth, Benedikt; Ritland, Melissa; Hoang, Linh T.; Loriot, Celine; Higa, Jason; Hansen, James E.; Felding, Brunhilde H.; Felding, Brunhilde H.; Siuzdak, Gary; Siuzdak, Gary Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids.. Cancer & Metabolism 2017, 5, 1 - 9.
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Roy, S.; Yin Axup, Jun; Forsyth, J. S.; Goswami, R. K.; Hutchins, B. M.; Bajuri, K. M.; Kazane, Stephanie A.; Smider, Vaughn V.; Felding-Habermann, Brunhilde; Sinha, S. C. SMI-Ribosome inactivating protein conjugates selectively inhibit tumor cell growth. Chemical Communications 2017, 53, 4234-4237.
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Weber, M. R.; Zuka, M.; Lorger, M.; Tschan, M.; Torbett, Bruce E.; Zijlstra, A.; Quigley, James P.; Staflin, K.; Eliceiri, B. P.; Krueger, J. S.; Marchese, P.; Ruggeri, Zaverio M.; Felding-Habermann, Brunhilde Activated tumor cell integrin avß3 cooperates with platelets to promote extravasation and metastasis from the blood stream. Thrombosis Research 2016, 140, S27-S36.
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Wold, Erik D.; Smider, Vaughn V.; Felding-Habermann, Brunhilde Antibody therapeutics in oncology. Immunotherapy 2016, 2, 108.
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Wold, Erik D.; Yin Axup, Jun; Felding-Habermann, Brunhilde; Smider, Vaughn V. Fc-small molecule antibody mimetics. Bioconjugate Chemistry 2015, 26, 2311-2314.
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