Lysosomes can play a major role in breast cancer invasion and metastasis, because they are a key mediator of protease routing, regulation, and secretion. Lysosomes contain diverse proteases that breast cancer cells utilize to invade through the extracellular matrix. Thus, non-invasive imaging of lysosomes may provide an innovative strategy for predicting and delineating the metastatic potential of breast tumors. We have recently developed novel methods to optically image lysosomes in living human breast cancer cells, and to quantitate specific lysosomal parameters. These methods now enable us to test our hypothesis that lysosomes, and lysosomal trafficking mediated by cytoskeletal components, plays an important role in breast cancer invasion and metastasis.
Our specific aims are: (1) To determine whether breast cancer cells recruit lysosomes to their cell surface to invade through the ECM, thereby either facilitating exocytic or endocytic processes, or both. (2) To assess the influence of the tumor microenvironment, characterized by hypoxia and extracellular acidity, on lysosomal trafficking in invading breast cancer cells, thereby evaluating the role of cytoskeletal components involved in lysosomal trafficking. (3) To develop and validate in vivo optical imaging of lysosomal parameters in human breast tumor xenograft models. Non-invasive, state-of-the-art cellular and in vivo optical imaging, such as confocal, total internal reflection, and multiphoton fluorescence microscopy will be employed. A panel of human breast cancer cell lines representing different stages of invasiveness and metastatic potential will be utilized in cell studies and tumor xenograft mouse models. Our research proposal will test whether imaging lysosomes in breast cancers can predict the metastatic potential of these tumors. Disruption of lysosomal trafficking may prove useful, therapeutically, to prevent metastasic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA112216-02
Application #
7140135
Study Section
Special Emphasis Panel (ZRG1-SBIB-F (02))
Program Officer
Menkens, Anne E
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$171,589
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Glunde, K; Jacobs, M A; Pathak, A P et al. (2009) Molecular and functional imaging of breast cancer. NMR Biomed 22:92-103
Serkova, Natalie J; Glunde, Kristine (2009) Metabolomics of cancer. Methods Mol Biol 520:273-95
Li, Cong; Greenwood, Tiffany R; Glunde, Kristine (2008) Glucosamine-bound near-infrared fluorescent probes with lysosomal specificity for breast tumor imaging. Neoplasia 10:389-98
Glunde, Kristine; Serkova, Natalie J (2006) Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism. Pharmacogenomics 7:1109-23
Glunde, Kristine; Jacobs, Michael A; Bhujwalla, Zaver M (2006) Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev Mol Diagn 6:821-9
Li, Cong; Greenwood, Tiffany R; Bhujwalla, Zaver M et al. (2006) Synthesis and characterization of glucosamine-bound near-infrared probes for optical imaging. Org Lett 8:3623-6