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Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Barbara M. Mueller
Associate Member

858.597.3849 - phone
858.597.3804 - fax
contact by email

Dr. Barbara Mueller is an Associate Member of Torrey Pines Institute for Molecular Studies.  She received her Dr. rer. nat. degree in Biology from the Christian-Albrechts-Universität in Kiel, Germany. She completed postdoctoral training at The Scripps Research Institute in La Jolla, CA in the laboratory of Dr. Ralph Reisfeld and then joined the Department of Immunology at Scripps as an Assistant Member/Professor. Between 2001 and 2009, she held positions at the La Jolla Institute for Molecular Medicine and the Sidney Kimmel Cancer Center. In 2009 Dr. Mueller jointed the Torrey Pines Institute for Molecular Studies.

Dr. Mueller's laboratory has received grant support from the National Institutes of Health, the Congressionally Directed Medical Research Program, and the California Breast Cancer Research Program.
Dr. Mueller is a member of several professional societies including the American Association for Cancer Research, the American Society for Cell Biology, and the American Association of Immunologists. Over the last decade Dr. Mueller has regularly reviewed manuscripts for many journals including Cancer Research, American Journal of Pathology, Blood, and Journal of Biological Chemistry.  She has also been asked to review research grants for different funding agencies including NIH, CDMRP, American Heart Association, and the Department of Veterans Affairs.  In addition to her appointments at non-profit research organizations, Dr. Mueller has also served as an advisor to several biopharmaceutical companies.

Biology of Cancer Metastasis

The research in the Mueller laboratory aims to understand cancer metastasis with a focus is on the crosstalk between cancer cells and the host environment. The laboratory is interested in basic research and in topics critical to patient care.

One focus of the laboratory is the role of the coagulation proteases and their receptors in cancer progression and metastasis. They have defined a critical role for tissue factor (TF) - the cell surface receptor and cofactor for the coagulation protease factor VIIa in angiogenesis and tumor progression. TF modulates cell behavior through a class of G-protein-coupled receptors known as protease-activated receptors (PAR). The laboratory is elucidating the signaling pathways downstream of TF/PAR as they relate to cancer using transgenic and transplanted cancer models. One goal is to determine whether TF and PARs can be therapeutic targets in cancer and, particularly, whether treatments can be developed that inhibit TF and/or PAR signaling rather than procoagulant function. These studies are conducted in collaboration with the Ruf laboratory at The Scripps Research Institute.

Brain metastasis is a major problem in many types of cancer including breast cancer and melanoma, and existing therapies are woefully ineffective. Together with Carol Kruse at The Burnham Institute the Mueller lab is testing whether therapeutic modalities that the Kruse group is developing for the treatment of primary gliomas are useful for cancer metastatic to the brain. These modalities include immune therapy, namely allo-reactive cytotoxic T cells as well as gene therapies based on replication competent retrovirus. Studies in models of breast cancer brain metastasis are ongoing.

Another interest is the role of myeloperoxidase (MPO) in breast cancer. Epidemiological studies link high MPO expression to decreased risk of recurrent breast cancer after adjuvant therapy but the underlying mechanisms are unknown. In collaboration with Wanda Reynolds at the Burnham Institute the Mueller lab is using transgenic mouse models of mammary tumors to understand the role of MPO in breast cancer progression and the mechanism(s) by which it may be protective.

Selected Publications

  1. Belting, M., Dorrell, M., Sandgren, S., Aguilar, E., Ahamed, J., Dorfleutner, A., Carmeliet, P., Mueller, B.M., Friedlander, M., and Ruf, W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nature Medicine, 10:502-509, 2004.
  2. Shi, X., Gangadharan, B., Brass, L.F., Ruf, W. and Mueller, B.M. Protease-activated receptor 1 (PAR1) and PAR2 contribute to tumor cell motility and metastasis. Molecular Cancer Res., 2:395-402, 2004
  3. Banka, C.L., Lund, C.V., Nguyen, M.T., Pakchoian, A.J., Mueller, B.M. and Eliceiri, B.P. Estrogen induces lung metastasis through a host compartment-specific response. Cancer Res., 66:3667-3672, 2006
  4. Liu, Y. and Mueller, B.M. Protease-activated receptor 2 regulates vascular endothelial growth factor expression in MDA-MB-231 human breast cancer cells via MAPK pathways. Biochem. Biophys. Res. Commun. 344:1263-1270, 2006
  5. Versteeg, H.H., Schaffner, F., Petersen H., Kerver, M., Ahamed, J., Felding-Habermann, B., Takada, Y., Mueller, B.M. and Ruf, W. Inhibition of tissue factor signaling suppresses tumor growth. Blood, 111:190-199, 2008

Publications

  1. Schaffner F., Versteeg, H.H., Kerver M., Ellis L., Andrade-Gordon, R., Mueller, B.M. and Ruf W. Protease Activated Receptor (PAR) 2 but not PAR1 signaling promotes the development of mammary adenocarcinoma in PYMT mice. Cancer Res. 68:7219-7227, 2008
  2. Tritz, R., Mueller, B.M., Hickey, M.J., Lin, A.H., Gomez, G.G., Hadwiger, P., Sah, D.W.Y., Muldoon L., Neuwelt, E.A., and Kruse, C.A. siRNA down-regulation of the PATZ1 gene in human glioma cells increases their sensitivity to apoptotic stimuli. Cancer Therapy 6:865-876, 2008
  3. Zhao, M., Mueller, B.M., DiScipio R., and Schraufstatter I. Akt plays an important role in breast cancer cell chemotaxis to CXCL12. Breast Cancer Res. Treatment 110:211-222, 2008
  4. Versteeg, H.H., Schaffner, F., Petersen H., Kerver, M., Ahamed, J., Felding-Habermann, B., Takada, Y., Mueller, B.M. and Ruf, W. Inhibition of tissue factor signaling suppresses tumor growth. Blood, 111:190-199, 2008
  5. Uusitalo-Jarvinen, H., Kurokawa, T., Mueller, B.M., Andrade-Gordon P., Friedlander M. and Ruf, W. Role of protease activated receptor 1 and 2 signaling in hypoxia-induced angiogenesis. Arterioscler. Thromb. Vasc. Biol., 27:1456-1462, 2007
  6. Liu, Y. and Mueller, B.M. Protease-activated receptor 2 regulates vascular endothelial growth factor expression in MDA-MB-231 human breast cancer cells via MAPK pathways. Biochem. Biophys. Res. Commun. 344:1263-1270, 2006
  7. Guo, F., Das, S., Mueller, B.M., Barbas III, C.F., Lerner, R.A. and Sinha S.C. Breaking the one antibody-one target axiom. Proc. Natl. Acad. Sci. USA, 103:11009-11014, 2006
  8. Banka, C.L., Lund, C.V., Nguyen, M.T., Pakchoian, A.J., Mueller, B.M. and Eliceiri, B.P. Estrogen induces lung metastasis through a host compartment-specific response. Cancer Res., 66:3667-3672, 2006
  9. Ahamed, J., Versteeg, H.H., Kerver M., Chen, V.M., Mueller, B.M., Hogg, P.J. and Ruf, W. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc. Natl. Acad. Sci. USA, 103:13932-13937, 2006
  10. Shi, X., Gangadharan, B., Brass, L.F., Ruf, W. and Mueller, B.M. Protease-activated receptor 1 (PAR1) and PAR2 contribute to tumor cell motility and metastasis. Molecular Cancer Res., 2:395-402, 2004
  11. Belting, M., Dorrell, M., Sandgren, S., Aguilar, E., Ahamed, J., Dorfleutner, A., Carmeliet, P., Mueller, B.M., Friedlander, M., and Ruf, W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nature Medicine, 10:502-509, 2004
  12. Jessani, N., Humphrey, M., McDonald, W.H., Niessen, S., Masuda, K., Gangadharan, B., Yates, III, J.R., Mueller, B.M. and Cravatt, B.F. Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo. Proc. Natl. Acad. Sci. USA, 101:13756-13761, 2004
  13. Riewald, M., Petrovan, R.J., Donner, A., Mueller, B.M. and Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:1880-1882, 2002
  14. Felding-Habermann, B., O-Toole, T. E., Smith, J.W., Fransvea, E. Ruggeri, Z.M., Ginsberg, M.H., Hughes, P.E., Pampori, N., Shattil, S.J., Saven, A. and Mueller, B.M. Integrin activation controls metastasis in human breast cancer. Proc. Natl. Acad. Sci. USA, 98:1835-1838, 2001
  15. Ott, I., Miyagi, Y., Miyazaki, K., Heeb, M.J., Mueller, B.M., Rao, L.V.M. and Ruf, W. Reversible regulation of the tissue factor pathway by glycosphingolipid-anchored TFPI. Arterioscler. Thromb. Vasc. Biol. 20:874-882, 2000
  16. Yebra, M., Goretzki, L., Pfeifer, M. and Mueller, B.M. Urokinase-type plasminogen activator binding to its receptor stimulates tumor cell migration by enhancing integrin-mediated signal transduction. Exp. Cell Res. 250:231-240, 1999
  17. Fischer, E.G., Riewald, M., Huang, H.-Y., Miyagi, Y., Kubota, Y., Mueller, B.M., and Ruf, W. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J. Clin. Invest. 104:1213-1221, 1999
  18. Goretzki, L. and Mueller, B.M. Low density lipoprotein receptor-related protein (LRP) interacts with a GTP-binding protein. Biochemical J. 336:381-386, 1998
  19. Mueller, B.M. and Ruf, W. Requirement for binding of catalytically active factor VIIa in tissue factor dependent experimental metastasis. J. Clin. Invest. 101:1372-1378, 1998
  20. 33. Dolman, C.S., Mueller, B.M., Lode, H.N., Xiang, R., Gillies, S.D. and Reisfeld, R.A. Suppression of human prostate carcinoma metastases in SCID mice by IL2 immunocytokine therapy. Clin. Can. Res. 4:2551-2557, 1998
  21. Ott, I., Fischer, E.G., Miyagi, Y., Mueller, B.M. and Ruf, W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin binding protein 280. J. Cell Biol. 140:1241-1253, 1998
  22. Wong, N.C., Mueller, B.M., Barbas III, C.F., Ruminski, P., Quaranta, V., Lin, E.C.K., and Smith, J.W. av integrins mediate adhesion and migration of breast carcinoma cell lines. Clin. Exp. Metastasis 16:50-61, 1998
  23. Goretzki, L. and Mueller, B.M. Receptor-mediated endocytosis of urokinase-type plasminogen activator is regulated by cAMP-dependent protein kinase. J. Cell Sci. 110:1395-1402, 1997
  24. Stahl, A. and Mueller, B.M. Melanoma cell migration on vitronectin: Regulation by components of the plasminogen activation system. Int. J. Cancer 71:116-122, 1997
  25. Yebra, M., Parry, G.C.N., Strömblad, S., Mackman, N., Rosenberg, S., Mueller, B.M. and Cheresh, D.A. Requirement of receptor bound urokinase-type plasminogen activator for integrin ανβ5-directed cell migration. J. Biol.Chem. 271:29393-29399, 1996
  26. Sivam, G.P., Martin, P.J., Reisfeld, R.A., and Mueller, B.M. Therapeutic efficacy of a doxorubicin immunoconjugate in a preclinical model of spontaneous metastatic melanoma. Cancer Res. 55:2352-2356, 1995
  27. Fischer, E.G., Ruf, W. and Mueller, B.M. Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. Cancer Res. 55:1629-1632, 1995
  28. Stahl, A. and Mueller, B.M. The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. J. Cell. Biol.129:335-344, 1995
  29. Mueller, B.M., Yu, Y.B., and Laug, W.E. Overexpression of plasminogen activator inhibitor 2 in human melanoma cells inhibits spontaneous metastasis in SCID mice. Proc. Natl. Acad. Sci. USA 92:205-209, 1995
  30. Montgomery, A.M.P., Mueller, B.M., Reisfeld, R.A., Taylor, S.M., DeClerck, Y.A. Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. Cancer Res. 54:5467-5473, 1994
  31. Stahl, A. and Mueller, B.M. Binding of urokinase to its receptor promotes migration and invasion of human melanoma cells in vitro. Cancer Res. 54:3066-3071, 1994
  32. Naramura, M., Gillies, S.D., Mendelsohn, J., Reisfeld, R.A., and Mueller, B.M. Mechanisms of cellular cytotoxicity mediated by a recombinant antibody-IL2 fusion protein against human melanoma cells. Immunol. Letters 39:91-99, 1994
  33. Sabzevari, H., Gillies, S.D., Mueller, B.M., Pancook, J.D. and Reisfeld, R.A. A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. Proc. Natl. Acad. Sci. USA 91:9626-9630, 1994
  34. Naramura, M., Gillies, S.D., Mendelsohn, J., Reisfeld, R.A., and Mueller, B.M. Therapeutic potential of chimeric and murine anti-epidermal growth factor receptor antibodies in a metastasis model for human melanoma. Cancer Immunol. Immunother. 37:343-349, 1993
  35. Montgomery, A.M.P., DeClerck, Y.A., Langley, K.E., Reisfeld, R.A., and Mueller, B.M. Melanoma-mediated dissolution of extracellular matrix: Contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways. Cancer Res. 53:693-700, 1993
  36. Sanders, L.C., Felding-Habermann, B., Mueller, B.M., and Cheresh, D.A. Role of αν integrins and vitronectin in human melanoma growth. Cold Spring Harbor Symp. Quant. Biol. 57:233-240, 1992
  37. Mueller, B.M., Reisfeld, R.A., Edgington, T.S. and Ruf, W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc. Natl. Acad. Sci. USA 89:11832-11836, 1992
  38. Schrappe, M., Bumol, T.F., Apelgren, L.D., Briggs, S.L., Koppel, G.A., Markowitz, D.D., Mueller, B.M., and Reisfeld, R.A. Long-term growth suppression of human glioma xenografts by chemoimmunoconjugates of desacetylvinblastine-hydrazide and monoclonal antibody 9.2.27. Cancer Res. 52:3838-3844, 1992
  39. Felding-Habermann, B., Mueller, B.M., Romerdahl, C.A., and Cheresh, D.A. Requirement of integrin aV gene expression for human melanoma tumorigenicity. J. Clin. Invest. 89:2018-2022, 1992
  40. Haenseler, E., Esswein, A., Vitols, K.S., Montejano, Y., Mueller, B.M., Reisfeld, R.A., and Huennekens, F.M. Activation of methotrexate-2-alanine by carboxypeptidase-A/mono-clonal antibody conjugate. Biochemistry 31:891-897, 1992
  41. Mueller, B.M., Romerdahl, C.A., Trent, J.M., and Reisfeld, R.A. Suppression of spontaneous melanoma metastasis in scid mice with an antibody to the epidermal growth factor receptor. Cancer Res. 51:2193-2198, 1991
  42. Dorai, H., Mueller, B.M., Reisfeld, R.A., and Gillies, S.D. Aglycosylated chimeric mouse/human IgG1 antibody retains some effector function. Hybridoma 10:211-217, 1991
  43. Mueller, B.M., Reisfeld, R.A., Silveira, M.H., Duncan, J.D., and Wrasidlo, W.A. Preclinical therapy of human melanoma with morpholino-doxorubicin conjugated to a monoclonal antibody directed against an integrin on melanoma cells. Antibody, Immunoconj. Radiopharm. 4:99-106, 1991
  44. Barker, E., Mueller, B.M., Handgretinger, R., Herter, M., Yu, A.L., and Reisfeld, R.A. Effect of a chimeric anti-ganglioside GD2 antibody on cell mediated lysis of human neuroblastoma cells. Cancer Res. 51:144-149, 1991
  45. Mueller, B.M., Wrasidlo, W.A., and Reisfeld, R.A. Antibody conjugates with morpholino doxorubicin and acid cleavable linkers. Bioconjugate Chem. 1:325-330, 1990
  46. Mueller, B.M., Reisfeld, R.A., and Gillies, S.D. Serum half-life and tumor localization of a chimeric antibody-deleted of the CH2 domain and directed against the disialoganglioside GD2. Proc. Natl. Acad. Aci. USA 87:5702-5705, 1990
  47. Hank, J.A., Robinson, R.R., Surfus, J., Mueller, B.M., Reisfeld, R.A., Cheung, N-K. and Sondel, P.M. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin-2. Cancer Res. 50:5234-5239, 1990
  48. Mueller, B.M., Romerdahl, C.A., Gillies, S.D., and Reisfeld, R.A. Enhancement of antibody dependent cytotoxicity with a chimeric anti-GD2 antibody. J. Immunol. 144:1382-1387, 1990
  49. Mueller, B.M., Wrasidlo, W.A., and Reisfeld, R.A. Determination of the number of e-amino groups available for conjugation of effector molecules to monoclonal antibodies. Hybridoma 7:453-456, 1988
  50. Mueller, B. and Mueller-Ruchholtz, W. Covalent conjugates of monoclonal antibody and cobra venom factor mediate specific cytotoxicity via alternative pathway of human complement activation. Leukemia Research 11:461-468, 1987
  51. Beigel, A., Steffens-Knutzen, R., Mueller, B., Schuhmacher, U., and Stein, H. Tracheal transplantation, III. Demonstration of transplantation antigens on the tracheal mucosa of inbred rat strains. Arch Otorhinolaryngol 241:1-8, 1984
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