The Project leader's and others studies in mouse models of cancer together with a growing body of clinical studies has led to a consensus that tumors associated macrophages (TAMs) play a major role in promoting malignancy in a wide variety of cancers. During the last granting period we have established a number of functions performed by macrophages that promote tumor progression and metastasis. These are through inflammation, matrix remodeling, tumor cell invasion, intravasation, angiogenesis and extravasation. In particular, we showed that macrophages were dramatically recruited to benign lesions and thereafter control the angiogenic switch that is required for the malignant transition. In addition, together with other members of the PPG, we showed that macrophages and tumor cells are in an obligate paracrine relationship that results in tumor migration, invasion and intravasation. We have also identified a unique population of macrophages that are required for seeding and persistent growth of metastases. Importantly we demonstrated that ablation of this population resulted in an inhibition of growth of established metastatic lesions. It is the aim of the current proposal to test out the requirement for both well-established and the newly identified pathways that we have defined in macrophage sub-populations, as well as unique mouse models developed during the last granting period, to identify the mechanistic basis of the macrophage-induced traits that lead to enhanced malignancy.
The specific aims are: 1. To provide the mechanistic basis for the functions of macrophage sub-populations in the tumor microenvironment 2. Define the molecular basis of macrophage regulation of angiogenesis. 3. Identify macrophage mediated mechanisms that promote metastatic seeding and persistent growth. Breast cancer is one of the most common causes of cancer death in women throughout the world. This is usually caused by metastatic disease. Our basic biology research using mouse models of cancer implicate TAMs as playing a major role in promoting the progression and metastasis of mammary cancer. Thus identifying the molecular basis for the macrophage actions proposed in this application will allow novel therapeutics targeted to these cells. Such therapeutics have an advantage over conventional ones aimed at tumor cells since these support cells do not exhibit the genetic instability of tumor cells and thus they are less likely to develop resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA100324-10
Application #
8376962
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$244,011
Indirect Cost
$97,016
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Al-Dimassi, Saleh; Salloum, Gilbert; Saykali, Bechara et al. (2016) Targeting the MAP kinase pathway in astrocytoma cells using a recombinant anthrax lethal toxin as a way to inhibit cell motility and invasion. Int J Oncol 48:1913-20
Balsamo, Michele; Mondal, Chandrani; Carmona, Guillaume et al. (2016) The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior. Sci Rep 6:35298
Chitu, Violeta; Gokhan, Şölen; Nandi, Sayan et al. (2016) Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System. Trends Neurosci 39:378-93
Leung, E; Xue, A; Wang, Y et al. (2016) Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene :
Knutsdottir, Hildur; Condeelis, John S; Palsson, Eirikur (2016) 3-D individual cell based computational modeling of tumor cell-macrophage paracrine signaling mediated by EGF and CSF-1 gradients. Integr Biol (Camb) 8:104-19
Pignatelli, Jeanine; Bravo-Cordero, Jose Javier; Roh-Johnson, Minna et al. (2016) Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena(INV)-initiated invadopodium formation. Sci Rep 6:37874
Wang, Yarong; Wang, Haoxuan; Li, Jiufeng et al. (2016) Direct visualization of the phenotype of hypoxic tumor cells at single cell resolution in vivo using a new hypoxia probe. Intravital 5:
Pollard, Jeffrey W (2016) Defining Metastatic Cell Latency. N Engl J Med 375:280-2
Rodriguez-Tirado, Carolina; Kitamura, Takanori; Kato, Yu et al. (2016) Long-term High-Resolution Intravital Microscopy in the Lung with a Vacuum Stabilized Imaging Window. J Vis Exp :
Lewis, Claire E; Harney, Allison S; Pollard, Jeffrey W (2016) The Multifaceted Role of Perivascular Macrophages in Tumors. Cancer Cell 30:18-25

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