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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100324-11A1
Application #
8666873
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Program Officer
Mohla, Suresh
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
$2,028,990
Indirect Cost
$814,026
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
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