Breast cancer is the most common malignancy in women worldwide and the leading cause of cancer related death. More than 1.2 million cases are diagnosed every year, affecting 10-12% of the female population and accounting for approximately 500,000 deaths per year worldwide. The primary cause of morbidity and mortality in women with breast cancer is metastasis. We currently do not have the technology to identify breast cancer patients with localized and regional disease who are at risk for metastatic disease. As a result, 80% of patients receive aggressive treatment that is necessary for patients with advanced breast cancer, although only about 10 to 15% of patients develop metastasis within 3 years of diagnosis. Given the significant short- and long-term complications of chemo- and radiotherapy, and its impact on quality of life of survivors, development of prognostic markers of metastasis and identification of anti-metastatic targets would greatly benefit women with breast cancer. The prognostic factors in current use include the number of positive lymph nodes, tumor size, grade and receptor status, and Mammaprint and OncotypeDX. Although all of these tools are in use in the management of breast cancer patients, they are derived from molecular sub-typing of whole tumor tissue and give no information about the presence of migratory and disseminating tumor cells within the tumor tissue as well as little insight into the specific mechanisms of metastasis. Hence, it is not clear how to improve their use within personalized treatment plans concerning risk and treatment response of metastasis. To define the mechanisms responsible for tumor cell migration and dissemination to distant sites, we developed multiphoton microscopes for observing and collecting the migratory and metastatic tumor cells from mammary tumors In live mice in real time. Using this technology we observed the importance of tumor cell-macrophage interactions in metastasis and discovered the human invasion signature (HIS), the expression profile of tumor cells during metastatic dissemination. We also identified the sites of tumor cell intravaation used for dissemination in vivo and named them TMEM for the Tumor MicroEnvironment of Metastasis. We hypothesize that tumor cells with increased activation of the pathways in the HIS can assemble TMEM, thereby increasing Intravasation. We have developed methods to measure the activation of the migration, adhesion and invadopod assembly pathways within the HIS and both intravasation and extravasation activities in vitro and in vivo which will allow us to test this hypothesis.

Public Health Relevance

The results of testing the hypothesis that tumor cells with increased activation of the pathways in the HIS can assemble TMEM, thereby increasing intravasation, have a high potential of being translational by application to determine risk of distant recurrence, and to personalize management of breast cancer patients at risk for metastatic disease. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100324-11A1
Application #
8669395
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Project Start
2003-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
11
Fiscal Year
2014
Total Cost
$199,154
Indirect Cost
$79,900
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Donnelly, Sara K; Miskolci, Veronika; Garrastegui, Alice M et al. (2018) Characterization of Genetically Encoded FRET Biosensors for Rho-Family GTPases. Methods Mol Biol 1821:87-106
Entenberg, David; Voiculescu, Sonia; Guo, Peng et al. (2018) A permanent window for the murine lung enables high-resolution imaging of cancer metastasis. Nat Methods 15:73-80
Norwood Toro, Laura E; Wang, Yarong; Condeelis, John S et al. (2018) Myosin-IIA heavy chain phosphorylation on S1943 regulates tumor metastasis. Exp Cell Res 370:273-282
Bresnick, Anne R (2018) S100 proteins as therapeutic targets. Biophys Rev 10:1617-1629
Suyama, Kimita; Yao, Jiahong; Liang, Huizhi et al. (2018) An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis. Cancer Res 78:103-114
Pastoriza, Jessica M; Karagiannis, George S; Lin, Juan et al. (2018) Black race and distant recurrence after neoadjuvant or adjuvant chemotherapy in breast cancer. Clin Exp Metastasis 35:613-623
Arwert, Esther N; Harney, Allison S; Entenberg, David et al. (2018) A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation. Cell Rep 23:1239-1248
Gizzi, Anthony S; Grove, Tyler L; Arnold, Jamie J et al. (2018) A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature 558:610-614
Karagiannis, George S; Condeelis, John S; Oktay, Maja H (2018) Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis 35:269-284
Yang, Ming; McKay, Daniel; Pollard, Jeffrey W et al. (2018) Diverse Functions of Macrophages in Different Tumor Microenvironments. Cancer Res 78:5492-5503

Showing the most recent 10 out of 234 publications