Overall Goals: Current prognostics used in assessing the risk of distant recurrence of breast cancer are not based on an understanding of mechanisms of tumor cell dissemination and metastatic seeding. As a result it is not clear how to improve their use within personalized treatment plans concerning risk of distant recurrence. It is also unclear how to use current prognostic metrics in anti-metastatic drug treatment trials. This PPG proposes to define the mechanisms responsible for tumor cell migration and dissemination to distant sites. We have discovered that tumor associated macrophages pair with tumor cells using a paracrine loop that drives tumor cell dissemination and metastasis. We have developed novel technologies to 1) directly observe the mechanisms of macrophage-dependent tumor cell dissemination in living mice in real time;2) collect, and expression profile the migratory and disseminating tumor cells and their helper macrophages cells;3) derive mutant cell lines and mice to test the mechanisms derived from these profiles in vivo and in vitro;and 4) use 1-3 to discover molecular mechanisms of dissemination and seeding of tumor cells. The projects of this PPG which will .address the above goals are: Project 1- """"""""Macrophage subtypes in Tumor Progression and Metastasis"""""""" will identify sub-populations of macrophages involved in progression allowing more specific drug targeting of the macrophage sub-population driving metastasis. Project 2- """"""""Macrophage signaling pathways enhancing tumor progression"""""""" will define signaling molecules that act in CSF-1 R downstream signaling pathways in tumor associated macrophages to effect tumor cell dissemination and metastasis. Project 3- """"""""ErbB3 and Intravasation during Metastasis"""""""" will study additional interaction networks between tumor cells and macrophages which regulate the initiation and maintenance of the paracrine loop that affects patient survival. Project 4- """"""""PI 3-Kinase and Metastasis"""""""" will provide important new insights into GPCR regulation of macrophage-tumor cell interactions. Project 5- """"""""Mechanisms of cell dissemination and metastatic seeding"""""""" will extend the new technologies and findings of the Projects and Cores of this Program Project to human breast tumor cells to investigate mechanisms behind tumor cell stromal cell interactions that contribute to tumor cell dissemination from primary breast tumors. The technology of the scientific cores is unique and innovative allowing analysis of mechanisms of tumor cell dissemination in live mice in real time and their reconstitution in vitro.
Relevance to public health: The proposed basic science studies of this PPG are aimed at defining the mechanisms of migration, dissemination and metastatic seeding. We believe that understanding of these mechanisms has a high potential of being translational and applicable to development of better prognostics and treatments for distant recurrence of breast cancer. However, the development of prognostics and therapeutics is beyond the resources and scope of this basic science PPG.
|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, ÅžÃ¶len; 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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