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Brunhilde Felding, Ph.D.

Associate Professor
Department of Chemical Physiology
California Campus
Laboratory Website
brunie@scripps.edu
(858) 784-2021

Scripps Research Joint Appointments

Department of Molecular and Experimental Medicine
Faculty, Graduate Program

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?
    and
  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.


Education

Ph.D., Philipps University Marburg, 1984

Selected References

Gay LJ, Felding-Habemann B (2011) Contribution of platelets to tumor metastasis. Nat Rev Cancer 11 (2): 123-34. PMID: 21258396

Felding-Habermann B, Gay LJ (2010) Platelets at the intersection of hemostasis, inflammation, and tumor metastasis. Proceedings of the Society of Toxicologic Pathology, STP/IFSTP Joint Symposium Report

Hutchins BM,Kazane SM, Staflin K, Forsyth JS, Felding-Habermann B, Smider VV, Schultz PG (2011) Selective Formation of Covalent Protein Heterodimers with a Non-natural Amino Acid. Chem Biol 18(3): 299-303. PMID: 21439474

Hutchins BM, Kazane SA, Staflin K, Forsyth JS, Felding-Habermann B, Schultz PG, Smider VV (2011) Site-specific coupling and sterically controlled formation of multimeric antibody Fab fragments using unnatural amino acids. J Mol Biol 406 (4): 595-603. PMID: 21237172

Lorger M, Lee H, Forsyth JS, Felding-Habermann B (2011) Comparison of in vitro and in vivo approaches to studying brain colonization by breast cancer cells. J Neurooncol 104(3): 686-96. PMID: 21359851

Gay LJ, Felding-Habermann B (2011) Platelets alter tumor cell attributes to propel metastasis: programming in transit. Cancer Cell 20(5): 553-554. PMID: 22094248

Lorger M, Felding-Habermann B (2012) Integrin Signaling in angiogenesis and metastatic progression to the brain. Chapter 13 in "Signaling Pathways and Molecular Mediators in Metastasis" S. Fatatis (ed), Springer Science and Business Media

Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim CH, Kazane SA, Halder R, Forsyth JS, Santidrian AF, Stafin K, Lu Y, Tran H, Seller AJ, Biroc SL, Szydlik A, Pinkstaff JK, Tian F, Sinha SC, Felding-Habermann B, Smider VV, Schultz PG (2012) Proc Natl Acad Sci USA 109(40): 16101-6. PMID: 22988081

Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, Yagi T, Felding-Habermann B. (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest [E-pub Feb 15, 2013] PMID: 23426180

Katz J, Krueger JS, Felding-Habermann B, Snyder EY (2009) Maintaining and engineering neural stem cells for delivery of genetically encoded therapy to brain tumors. Meth Mol Biol 568:249-59. PMID: 19582432

Goswami RK, Haung ZZ, Forsyth JS, Felding-Habermann B, Sinha SC (2009) Multiple catalytic aldolase antibodies suitable for chemical programming. Bioorg Med Chem Lett 19(14) :3821 -24. PMID: 19428247

Wurdak H, Zhu S, Romero A, Lorger M, Watson J, Chiang C, Zhang J, Natu VS, Lairson LL, Walker JR, Trussel CM, Harsh GR, Vogel H, Felding-Habermann B, Orth AP, Miraglia LJ, Rines DR, Skirball SL, Schultz PG (2010) An RNAi screen identified TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell Stem Cell Jan 8 ;6 (1):37-47. PMID: 20085741

Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of brain metastasis. Am J Pathol 176(6) :2958 -71. PMID: 20382702

Staflin K, Krueger JS, Hachmann J, Lorger M, Forsyth JS, Steiniger SCJ, Mee J, Pop C, Salvesen G, Janda KD, Felding-Habermann B (2010) Targeting activated integrin a v b 3 with patient derived antibodies impacts late-stage multiorgan metastasis. Clin Exp Metastasis 27(4) :217 -31. PMID: 20225083

Felding-Habermann B, Gay LJ (2010) Platelets at the intersection of hemostasis, inflammation, and tumor metastasis. Proceedings of the Society of Toxicologic Pathology, STP/IFSTP Joint Symposium Report

Gay LJ, Felding-Habemann B (2011) Contribution of platelets to tumor metastasis. Nat Rev Cancer 11 (2): 123-34. PMID: 21258396

Hutchins BM,Kazane SM, Staflin K, Forsyth JS, Felding-Habermann B, Smider VV, Schultz PG (2011) Selective Formation of Covalent Protein Heterodimers with a Non-natural Amino Acid. Chem Biol 18(3): 299-303. PMID: 21439474

Hutchins BM, Kazane SA, Staflin K, Forsyth JS, Felding-Habermann B, Schultz PG, Smider VV (2011) Site-specific coupling and sterically controlled formation of multimeric antibody Fab fragments using unnatural amino acids. J Mol Biol 406 (4): 595-603. PMID: 21237172

Lorger M, Lee H, Forsyth JS, Felding-Habermann B (2011) Comparison of in vitro and in vivo approaches to studying brain colonization by breast cancer cells. J Neurooncol 104(3): 686-96. PMID: 21359851

Gay LJ, Felding-Habermann B (2011) Platelets alter tumor cell attributes to propel metastasis: programming in transit. Cancer Cell 20(5): 553-554. PMID: 22094248

Lorger M, Felding-Habermann B (2012) Integrin Signaling in angiogenesis and metastatic progression to the brain. Chapter 13 in "Signaling Pathways and Molecular Mediators in Metastasis" S. Fatatis (ed), Springer Science and Business Media

Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim CH, Kazane SA, Halder R, Forsyth JS, Santidrian AF, Stafin K, Lu Y, Tran H, Seller AJ, Biroc SL, Szydlik A, Pinkstaff JK, Tian F, Sinha SC, Felding-Habermann B, Smider VV, Schultz PG (2012) Proc Natl Acad Sci USA 109(40): 16101-6. PMID: 22988081

Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, Yagi T, Felding-Habermann B. (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest [E-pub Feb 15, 2013] PMID: 23426180

Staflin K, Krueger JS, Hachmann J, Lorger M, Forsyth JS, Steiniger SCJ, Mee J, Pop C, Salvesen G, Janda KD, Felding-Habermann B (2010) Targeting activated integrin a v b 3 with patient derived antibodies impacts late-stage multiorgan metastasis. Clin Exp Metastasis 27(4) :217 -31. PMID: 20225083

Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of brain metastasis. Am J Pathol 176(6) :2958 -71. PMID: 20382702

Wurdak H, Zhu S, Romero A, Lorger M, Watson J, Chiang C, Zhang J, Natu VS, Lairson LL, Walker JR, Trussel CM, Harsh GR, Vogel H, Felding-Habermann B, Orth AP, Miraglia LJ, Rines DR, Skirball SL, Schultz PG (2010) An RNAi screen identified TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell Stem Cell Jan 8 ;6 (1):37-47. PMID: 20085741

Goswami RK, Haung ZZ, Forsyth JS, Felding-Habermann B, Sinha SC (2009) Multiple catalytic aldolase antibodies suitable for chemical programming. Bioorg Med Chem Lett 19(14) :3821 -24. PMID: 19428247

Katz J, Krueger JS, Felding-Habermann B, Snyder EY (2009) Maintaining and engineering neural stem cells for delivery of genetically encoded therapy to brain tumors. Meth Mol Biol 568:249-59. PMID: 19582432

Staflin K, Krueger JS, Hachmann J, Lorger M, Forsyth JS, Steiniger SCJ, Mee J, Pop C, Salvesen G, Janda KD, Felding-Habermann B (2010) Targeting activated integrin a v b 3 with patient derived antibodies impacts late-stage multiorgan metastasis. Clin Exp Metastasis 27(4) :217 -31. PMID: 20225083

Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of brain metastasis. Am J Pathol 176(6) :2958 -71. PMID: 20382702

Wurdak H, Zhu S, Romero A, Lorger M, Watson J, Chiang C, Zhang J, Natu VS, Lairson LL, Walker JR, Trussel CM, Harsh GR, Vogel H, Felding-Habermann B, Orth AP, Miraglia LJ, Rines DR, Skirball SL, Schultz PG (2010) An RNAi screen identified TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell Stem Cell Jan 8 ;6 (1):37-47. PMID: 20085741

Goswami RK, Haung ZZ, Forsyth JS, Felding-Habermann B, Sinha SC (2009) Multiple catalytic aldolase antibodies suitable for chemical programming. Bioorg Med Chem Lett 19(14) :3821 -24. PMID: 19428247

Katz J, Krueger JS, Felding-Habermann B, Snyder EY (2009) Maintaining and engineering neural stem cells for delivery of genetically encoded therapy to brain tumors. Meth Mol Biol 568:249-59. PMID: 19582432

Katz J, Krueger JS, Felding-Habermann B, Snyder EY (2009) Maintaining and engineering neural stem cells for delivery of genetically encoded therapy to brain tumors. Meth Mol Biol 568:249-59. PMID: 19582432

Lorger M, Krueger JS, O'Neal M, Staflin K, Felding-Habermann B (2009) Activation of tumor cell integrin a v b 3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci USA 106(26): 10666-71. PMID: 19541645

Versteeg HH, Schaffner F, Kerver M, Petersen HH, Ahamed J, Felding-Habermann B, Takada Y, Mueller BM, and Ruf W (2008) Inhibition of tissue factor signaling suppresses tumor growth. Blood 111(1) :190 -9. PMID: 17901245

Jain S, Zuka M, Liu J, Russell S, Dent J, Guerrero JA, Forsyth J, Maruszak B, Gartner TK, Felding-Habermann B, and Ware J. (2007) Platelet glycoprotein Ib a supports experimental lung metastasis . Proc Natl Acad Sci USA 104(21): 9024-8. PMID: 17494758

Liu Y, Steiniger SC, Kim Y, Kaufmann GF, Felding-Habermann B, Janda KD (2007) Mechanistic studies of a peptidic GRP78 ligand for cancer cell-specific drug delivery. Mol Pharm . 4(3) :435 -47. PMID: 17373820

Palmieri D, Chambers AF, Felding-Habermann B, Huang S, Steeg PS (2007) The biology of metastasis to a sanctuary site. Clin Cancer Res 13(6): 1656-1662. PMID: 17363518

Chen EI, Hewel J, Krueger JS, Weber MR, Tiraby C, Kralli A, Becker K, Yates JR III, Felding-Habermann B. (2007) Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67(4): 1472-1486. PMID: 17308085

Felding-Habermann, B., Lerner, R.A., Lillo, A., Zhuang, S., Weber, M.R., Arrues, S., Gao, C., Mao, S., Saven, A., Janda, K.D. (2004) Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis. Proc Natl Acad Sci USA 101: 17210-17215. PMID: 15563590

Rolli M, Fransvea E, Pilch J, Saven A, Felding-Habermann B (2003) Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc Natl Acad Sci USA 100(16): 9482-9487. PMID: 12874388

Felding‑Habermann B, O'Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, Hughes PE, Pampori N, Shattil SJ, Saven A, Mueller BM (2001) Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci U S A 98(4) :1853 ‑1858. PMID: 11172040

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