Cancer

Cancer

Overview

Tumors are made up of cancer cells and also of normal cell types and extracellular molecules that surround, support and feed the cancer cells. There is abundant communication between the cancer cells and the normal elements; and a tumor can change its environment, and the environment can affect how a tumor grows and spreads. Dr. Mueller’s research group studies the tumor microenvironment.

About one third of all people with cancer die of cachexia (severe muscle wasting). Cachexia affects people at the later stages of disease and causes debilitating muscle weakness. It is associated with reduced response to therapy and poor prognosis.

Learn more about cachexia

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Studies

The Mueller group

Dr. Mueller’s group is mainly focused on breast cancer and on a group of receptors, called protease receptors. Her lab is working to understand how these protease receptors get activated in the tumor environment and thereby make the cancer more aggressive. In addition they are also investigating whether these receptors can be new targets for the treatment of advanced cancer.

Dr. Mueller and her collaborators have defined a critical role for tissue factor (TF), the cell surface receptor and cofactor for the coagulation protease factor VIIa, in tumor progression. They were the first to show that TF and coagulation protease signaling networks contribute to tumor growth, tumor-induced angiogenesis and metastasis. More recently they are defining the functions of TF and the endothelial protein C receptor (EPCR) in subsets of cancer stem cells. Her work also contributed to the understanding of the extracellular matrix modifying proteases of the fibrinolytic system. Earlier studies focused on urokinase and the urokinase receptor. Recent studies are uncovering roles for the plasminogen receptor in function of normal breast tissue and in breast cancer progression.

Dr. Mueller also has a longstanding interest in translating basic research into clinical applications. She has been involved in developing an anti-ganglioside antibody, which has recently completed phase III clinical evaluation for neuroblastoma, and an anti-tissue factor antibody for treatment of solid tumors, which is currently moving toward clinical testing.

The ElShamy group

Dr. ElShamy’s interests encompass basic, clinical and translational cancer research and research programs in his laboratory focus on identifying and improving treatments for breast and ovarian cancers, especially metastatic diseases. The ElShamy research group is focused on tackling breast cancer as an interactive entity composed of tumor cells and their microenvironment. The tumor microenvironment contains a variety of activated entities, such as mesenchymal stem cells and macrophages, which are intimately involved in increasing tumor progression and cancer spreading to other organs. The ElShamy approach aims to therapeutically target both the microenvironment and the tumor cells to achieve a higher level of remission.

The ongoing research conducted by the ElShamy group is based on the hypothesis that tumor cell dissemination and metastasis is an early event and not an end point of the disease. If that hypothesis is correct, current treatment options that are effective in killing primary tumor cells will fail to target and remove the true patient killers, the already disseminated metastatic precursors. Dr. ElShamy studies metastasis as part of the earliest breast cancer lesions. The hope is that, if successful, this information will allow us to develop novel therapeutic regimens to block tumor progression, and therapeutic resistance.

Select Publications

Miles, L.A., Lighvani, S., Baik, N., Parmer, C.M., Khaldoyanidi, S., Mueller, B.M., and Parmer, R.J. (2014). New insights into the role of Plg-RKT in macrophage recruitment. Int. Rev. Cell. Mol. Biol. 2014; 309:259-302.

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Schaffner F, Yokota N, Carneiro-Lobo T, Kitano M, Schaffer M, Anderson GM, Mueller BM, Esmon CT, and Ruf W. Endothelial Protein C Receptor Function in Murine and Human Breast Cancer Development. PLoS One. 2013;8:e61071.

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Liu E, Samad F, Mueller, BM. Local adipocytes enable estrogen-dependent breast cancer growth: Role of leptin and aromatase. Adipocyte. 2013;2:165–169.

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Belting, M., Dorrell, M.I., 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, 2004; 10:502-509.

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Versteeg HH, Schaffner F, Petersen H, Kerver M, Ahamed, J, Felding-Habermann B, Takada Y, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296(5574):1880-2.

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Mueller, B, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor dependent experimental metastasis. J Clin Invest. 1998;101:1372–8.

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Blanchard Z, Paul BT, Craft B, ElShamy WM. BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers. Breast Cancer Res. 2015 Jan 13;17:5.

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Sinha A, Paul BT, Sullivan LM, Sims H, El Bastawisy A, Yousef HF, Zekri AN, Bahnassy AA, ElShamy WM. BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions. Oncotarget. 2017 Feb 7;8(6):10114-10135.

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Gardner L, Malik R, Shimizu Y, Mullins N, ElShamy WM. Geminin overexpression prevents the completion of topoisomerase IIα chromosome decatenation, leading to aneuploidy in human mammary epithelial cells. Breast Cancer Res. 2011 May 19;13(3):R53.

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Blanchard Z, Mullins N, Ellipeddi P, Lage JM, McKinney S, El-Etriby R, Zhang X, Isokpehi R, Hernandez B, Elshamy WM. Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. PLoS One. 2014 Apr 30;9(4):e95663.

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Ananthula S, Sinha A, El Gassim M, Batth S, Marshall GD Jr, Gardner LH, Shimizu Y, ElShamy WM. Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhance aggressiveness in triple negative breast cancers. Oncotarget. 2016 Apr 12;7(15):20869-89.

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Ryan D, Sinha A, Bogan D, Davies J, Koziol J, ElShamy W. A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment. Oncotarget. 2017 8:103182-103206.

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Rothmeier, A. S., Liu, E., Chakrabarty, S., Disse, J., Mueller, B. M., Østergaard, H., & Ruf, W. Identification of the coagulation factor VIIa integrin binding site required for pro-angiogenic PAR2 signaling. Blood. 2018. 131:674-685.

Miles, L.A., Baik, N., Lighvani, S., Khaldoyanidi, S., Varki, N.M., Bai, H., Mueller, B.M., and Parmer, R.J. Deficiency of plasminogen receptor, Plg-RKT, causes defects in plasminogen binding and inflammatory macrophage recruitment in vivo. J. Thromb Hemost. 2017 15:155-162.

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Miles, L.A., Baik, N., Bai, H., Makarenkova, H.P., Kiosses, W.B., Krajewski, S., Castellino, F.J., Valenzuela. A., Varki, N.M., Mueller, B.M. and Parmer, R.J. The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation. J Thromb Haemost. 2018 doi: 10.1111/jth.13988. [Epub ahead of print]

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Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

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