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Dr. Mueller’s research aims to understand cancer progression and metastasis with a focus on the crosstalk between cancer cells and the host environment. The laboratory uses in vitro and in vivo models for basic and translational research.
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.
Ad hoc reviewer of manuscripts for:
Ad hoc reviewer of grant applications for:
Selected Publications (10 of 71)
Pending - Compositions and Methods for Controlling Tissue Factor Signaling Specificity. Inventors: Wolfram Ruf, Jassimuddin Ahamed, Henrik Versteeg and Barbara M. Mueller.