Barbara M. Mueller

Dr. Barbara Mueller’s laboratory aims to understand cancer progression and metastasis with a focus on the crosstalk between cancer cells and the host environment. She has a long-standing interest in the role of the serine proteases and their receptors in cancer, and her group has defined a critical role for tissue factor (TF) in angiogenesis and tumor progression. TF is the cell surface receptor and cofactor for the coagulation protease factor VIIa, and modulates cell behavior through a class of receptors known as protease-activated receptors (PAR). The laboratory is using transgenic and transplanted cancer models to elucidate the signaling pathways downstream of TF/PAR as they relate to cancer. 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 Dr. Wolfram Ruf at The Scripps Research Institute.

Figure 1. TF signaling in cancer cells involves PAR2 and integrins and has multiple effects on angiogenesis and tumor progression. TF is constitutively associated with laminin-binding beta(1) integrins that support TF-VIIa-PAR2 signaling leading to upregulation of pro-angiogenic and immune modulatory cytokines and growth factors. Deficiency of PAR2, but not of the thrombin receptor PAR1, delays spontaneous breast cancer development and the angiogenic switch in mice. In addition, human xenograft breast cancer growth and angiogenesis is suppressed by selective antibody inhibition ofTF-VIIa-PAR2 signaling, but not by blocking TF initiated coagulation. From Ruf et al., Thromb. Res. 2009

Another interest is the role of myeloperoxidase (MPO) in breast cancer. Epidemiological studies have linked high MPO expression to a decreased risk of recurrent breast cancer after adjuvant therapy, but the underlying mechanisms are unknown. In collaboration with Dr. Wanda Reynolds at the Sanford-Burnham Medical Research 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 protect.

Substantial clinical evidence indicates that obesity is a risk factor for the development of breast cancer. In fact, obesity at the time of breast cancer diagnosis has a negative impact on prognosis for both premenopausal and postmenopausal women. Recently the Mueller lab has begun to develop models to study the interaction between cancer cells and adipocytes in the breast microenvironment, and to identify the factors by which local adipocytes contribute to the development of estrogen receptor-positive as well as so-called triple-negative breast cancer. This project is being performed in collaboration with the laboratory of Dr. Fahumiya Samad at TPIMS.

Figure 2. Local adipocytes support growth of ER-positive breast cancer in a mouse model. MCF-7human breast tumors grown in F442A fat pads in SCID mice. In panels A-C fairly uniform small tumor cells have blue violet nuclei and pink cytoplasms (T: tumor). Mature adipocytes appear as empty profiles since the large central fat droplets dissolve during tissue processing (A: adipocytes). Gross morphology of a MCF-7/F442A tumor (arrow) in D.

Dr. Mueller received her Dr. rer. nat. degree in Biology/Immunology 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 (NIH), the Congressionally Directed Medical Research Program (CDMRP), the California Breast Cancer Research Program (CBCRP) and the Menopause & Women’s Health Research Program.

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.

Education

• 1987-1989         The Scripps Research Institute, La Jolla, CA, Postdoctoral Fellow, Tumor Immunology
• 1987                     University of Kiel, Kiel, Germany, Ph.D. (Dr. rer. nat.) Biology/Immunology
• 1982                     University of Kiel, Kiel, Germany, M.S. (Diplom) Biology/ Zoology

Positions

• 2009 – present   Associate Member, Torrey Pines Institute for Molecular Studies, San Diego, CA
• 2007 – 2009        Associate Professor, Vascular Biology & Tumor Biology Programs Sidney Kimmel Cancer Center, San Diego, CA
• 2001 – 2007       Associate Professor, Cancer Biology Division, La Jolla Institute for Molecular Medicine, San Diego, CA
• 1991 – 2001        Assistant Professor/Assistant Member, Department of Immunology, The Scripps Research Institute, La Jolla, CA
• 1990 – 1991       Senior Research Associate, Department of Immunology, The Scripps Research Institute, La Jolla, CA

Professional Affiliations

• Member, American Association for Cancer Research
• Member, American Society for Cell Biology
• Member, American Association of Immunologists

Honors & Awards

• 1987 – 1989        Postdoctoral Fellowship, Deutsche Forschungsgemeinschaft
• 1994                     Junior Faculty Travel Award, Gordon Conference on Thrombolysis, Ventura, CA
• 1994                     Chairperson of Poster Discussion Session, “Melanoma Biology”, AACR Annual Meeting, San Francisco, CA
• 1995                     Member, Special Review Committee, NCI, Development Grantsfor New Research Programs in Prostate Cancer
• 1995- 1998          Junior Faculty Research Award, American Cancer Society
• 1996                     Moderator of Session on “Angiogenesis and Cancer,” Gordon Conference on Thrombolysis, Ventura, CA
• 1996                     Member, Special Study Section, NIH, SBIR, Multidisciplinary Special Emphasis Panel
• 1996 - 2001         Member, Vascular Biology Affinity Group, TSRI
• 1997                     Organizing Committee, VIth International Workshop on Molecular and Cellular Biology of Plasminogen Activation
• 1998 - 2001         Faculty, NCI Training Grant, "Vascular Biology in Cancer"
• 2002                     Invited attendee, “Caveolae and lipid rafts in cancer”, Workshop organized by the Tumor Biology and Metastasis Branch, NIH/NCI, Washington DC
• 2002                     Organizing Committee, XVIII International Congress on Fibrinolysis and Proteolysis
• 2002                     Reviewer, USAMRMC/CDMRP Breast Cancer Research Program, Pathobiology-3 Panel
• 2003                     Ad hoc member, Subcommittee A- Cancer Centers, NCI Initial Review Group
• 2003                     Reviewer, USAMRMC/CDMRP Breast Cancer Research Program, Pathobiology-2 Panel
• 2004                     Reviewer, AHA, Western Review Consortium, Cardiovascular Development, Basic Cell & Molecular Biology Peer Review Panel
• 2004                     Reviewer, USAMRMC/CDMRP Breast Cancer Research Program, Pathobiology-2 Panel
• 2005                     Reviewer, AHA, Western Review Consortium, Cardiovascular Development, Basic Cell & Molecular Biology Peer Review Panel
• 2005                     Reviewer, USAMRMC/CDMRP Breast Cancer Research Program, Pathobiology Concept Panel
• 2006                     Reviewer, AHA, Western Review Consortium, Cardiovascular Development, Basic Cell & Molecular Biology Peer Review Panel
• 2006                     Scientific Review Administrator (Consultant), Constella Health Sciences,CDMRP Breast Cancer Research Program, Endocrinology Panel
• 2006                     Chair, State of the Art Plenary Session: Proteomics, 18^th International Congress on Fibrinolysis and Proteolysis: Proteolysis in the Postgenomic Area
• 2007                     Reviewer, AHA, Western Review Consortium, Cardiovascular Development, Basic Cell & Molecular Biology Peer Review Panel
• 2007                     Scientific Review Administrator (Consultant), Constella Health Sciences, CDMRP Breast Cancer Research Program, Immunological Sciences Panel
• 2007                     Reviewer, AHA, Young Investigators Forum, San Diego CA
• 2008                     Scientific Review Officer (Consultant), Constella Health Sciences, CDMRP Prostate Cancer Research Program, Pathobiology Panel
• 2008                     Member, AACR Centennial Predoctoral and Postdoctoral Fellowship Grants Committee

Ad hoc reviewer of manuscripts for:

• Cancer Research
• Clinical Cancer Research
• The American Journal of Pathology
• The Journal of Biological Chemistry
• The Journal of Cell Biology
• The Journal of Immunology
• Blood
• The International Journal of Cancer
• Experimental Cell Research
• Oncogene and others

Ad hoc reviewer of grant applications for:

• The Department of Veterans Affairs
• The Dutch Cancer Society
• The Israel Science Foundation
• Cancer Research UK.

Selected Publications (10 of 71)

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. Tritz, R., Hickey, M.J., Lin, A.H., Hadwiger, P., Sah, D.W.Y., Neuwelt, E.A., Mueller, B.M., and Kruse, C.A. FAPP2 gene downregulation increases tumor sensitivity to Fas-induced apoptosis. Biochem. Biophys. Res. Commun. 383:167-171, 2009

Patents

Pending - Compositions and Methods for Controlling Tissue Factor Signaling Specificity. Inventors:  Wolfram Ruf, Jassimuddin Ahamed,  Henrik Versteeg and Barbara M. Mueller.