Metastasis represents the major cause of mortality in, cancer patients. According to most current models of metastasis, interactions between tumor cells and the stromal microenvironment involving adhesion, proteolysis, growth factor and cytokine secretion and chemotaxis are key events at the cellular level driving the traversal of basement membrane barriers, migration and intravasation. Until recently, however, the technology has not existed to observe and manipulate these events at the cellular and molecular levels in vivo. The interdisciplinary projects and specialized cores of this program project, some with unique technologies, have provided the opportunity to investigate these events at the molecular and cellular levels in vivo. During the previous funding period the members of this program have demonstrated that macrophages are necessary for enhancing the motility and invasion of tumor cells in primary mammary tumors of rats and mice. We have shown how tumor cells and host macrophages both contribute, in a highly interactive process, to the intercellular signaling necessary for tumor cell motility, invasion, intravasation and metastasis. We have discovered the signaling pathways in macrophages and tumor cells that contribute to the signaling, motility and chemotaxis behaviors that generate the invasive phenotype and identified an invasion signature that uniquely defines invasive tumor cells in rat and mouse mammary tumors. In this competing continuation application we propose to extend and broaden the new insights derived during the previous funding period: 1) to identify the various subpopulations of macrophages present in primary tumors and metastatic tumors, and how they differentially affect angiogenesis, intravasation and extravasation;2) to define, at the molecular level, the specific colony stimulating factor (CSF1) and erbB family phosphotyrosine-associated pathways that regulate growth factor production, chemotaxis, intravasation and metastasis;3) to identify additional cytokines, growth factors, and stromal cells involved in initiating the paracrine loop between macrophages and tumor cells and the cellular sources of these cytokines and growth factors;4) investigate chemotaxis and motility pathways in tumor cells and macrophages that determine cell polarity and migration efficiency at the molecular level;5) extend the invasion signature discovered in rats and mice to human breast tumors by adapting the technology developed during the previous funding period to human cell line-derived tumors and human tumors from patients transplanted into mouse hosts;and 6) evaluate biomarkers derived from the human and mouse invasion signatures for their ability to define landmarks involved in invasion and intravasation in human breast tumors and predict the outcome of the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA100324-10
Application #
8302467
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Mohla, Suresh
Project Start
2003-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$2,016,840
Indirect Cost
$801,876
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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
Cabrera, Ramon M; Mao, Serena P H; Surve, Chinmay R et al. (2018) A novel neuregulin - jagged1 paracrine loop in breast cancer transendothelial migration. Breast Cancer Res 20:24
Meirson, Tomer; Genna, Alessandro; Lukic, Nikola et al. (2018) Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget 9:22158-22183

Showing the most recent 10 out of 234 publications