Breast cancer is the most common malignancy in women worldwide. While advance have been made in treatment this disease still accounts for the second largest number of cancer deaths in women in the US. These deaths are largely due to metastatic disease. This proposal is based upon observations by project leaders (PL) and other members of the PPG that tumor associated macrophages (TAMs) play a critical role in promoting the rate-limiting steps of metastasis - tumor cell intravasation and extravasation. Central to these observations was the definition by the PL of TAM sub-populations defined by their transcriptome and cell surface markers. Thus different populations have individual functions including in the primary tumor the stimulation of angiogenesis, tumor cell invasion and intravasation as well as at metastatic sites extravasation and persistent growth. In this proposal we have three specific aims:
Aim 1 : Mechanisms for Monocyte Recruitment and Macrophage Differentiation in the Primary Tumor. In this aim the mechanism of recruitment and differentiation of the different populations to the primary tumor will be studied with a particular focus upon those macrophages that stimulate invasion and intravasation. We will use novel methods for fate mapping macrophages to explore their origin and plasticity in the tumor.
Aim 2 : Molecular basis for the Promotion of Extravasation by of Metastasis Associated Macrophages.
This aim will define the signaling pathways that convert macrophages into those that promote extravasation of tumor cells. It will discover the mechanism whereby macrophages enable tumor cells to egress through the endothelial layer.
Aim3 : Definition of Pro-Tumoral Functions of Human breast Cancer TAMs Studies will be translated from mouse models into human breast cancer. Human TAMs from various disease sub-types will be isolated followed by ex vivo assays for function. These assays together with transcriptional profiles will define signaling pathways and determine whether they parallel those found in mice. Together these studies will enable therapeutic targets aimed at sub-populations of macrophages rather than the pan- macrophage therapeutics currently in trial that have toxicities because that target all resident macrophages.

Public Health Relevance

In the US -250,000 new cases of invasive ductal breast carcinoma are diagnosed each year with 40,000 deaths. Over the last decade statistics show an improvement in survival for women with local disease but no change for those with metastatic disease. This depressing statistic demands new therapeutic approaches. In this application we propose that one strategy to improve treatment is to target the tumor microenvironment and particularly the macrophages within it in order to remove their pro-tumor support.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 192 publications