This project will focus on novel interactions between breast cancer cells and tumor associated macrophages that contribute to increased tumor malignancy. Our previous studies have defined an EGFR/CSF1R paracrine loop operating between these two cell types and its role in invasion and intravasation. In this proposal we will evaluate additional novel interactions between tumor cells and macrophages which could be critical for patient survival. We propose that neuregulins and CXCR2 ligands secreted by tumor cells activate ErbB3 and CXCR2 on macrophages, resulting in increased production of AREG, HBEGF and angiogenic factors by macrophages. HBEGF and AREG simulate tumor cell invasiveness, while the angiogenic factors disrupt the endothelial barrier, with the combined results leading to increased intravasafion. We propose three specific aims in which we will test these hypotheses.
In Aim 1 we will evaluate the role of stimulation of macrophage ErbB3 by neuregulins secreted by tumor cells.
In Aim 2 we will evaluate the role of macrophage CXCR2.
In Aim 3, we will examine the roles of HBEGF, AREG and angiogenic factors produced by macrophages. The project will integrate the use of in vitro and in vivo models of intravasation and extravasation provided by Cores A, B, and C to study the role of these pathways in breast cancer metastasis. Close collaboration with the other projects in the PPG will facilitate evaluation of macrophage polarizafion and dynamics during invasion and metastasis (Project 1), mechanisms of CSFl R synergy with ErbBS and GPCR signaling (Projects 2 and 4), and the roles played by the ErbB3/CXCR2 pathways contributing to the various steps in transendothelial migration (Project 5). The ultimate goal is to identify new options for prognosis and therapeutic interventions.

Public Health Relevance

Breast cancer is the second highest cause of death due to cancer in women, demonstrating the need to develop new methods for treating it. This project will test the roles of specific signaling interactions between tumor cells and macrophages with the long term goal of improving prognosis and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100324-11A1
Application #
8669393
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
$274,221
Indirect Cost
$110,017
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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