It is believed that the lung is a permissive organ for the seeding of certain metastasizing tumors. Recent studies have supported this, finding that distal primary tumors instigate bone marrow-derived cell (BMDC) migration into the lung, forming a pre-metastatic niche (PreMN), and that these cells are crucial for robust and efficient metastasis. These studies have led to a growing recognition of the importance of the immune system and the pulmonary PreMN in lung metastasis, but many important questions remain and have been hitherto inaccessible. Most notably, there has been no direct way of assessing the behavior and fate of DTCs within the lung PreMN versus normal 'less-permissive'lung tissue. Further, the PreMN contains a diverse set of immune cells and the effect of interaction with these populations on DTC survival is unknown. In order to understand and therapeutically target pulmonary metastasis we must first address these crucial questions, in vivo The basis for this R21 exploratory grant is to apply novel real-time intravital imaging approaches to understand how the lung deals with incoming cells. Of particular relevance are to understand why and how metastatic cells survive in the environment and how host-cells 'receive'them and protect them from normal elimination of cells from the vasculature. We hypothesize that normal removal of cells from microvasculature is a repair process which metastatic cells, helped by host cells, extend in duration to achieve successful colonization. The overall success of this project will be defined by our knowledge of the spatiotemporal landscape that metastatic cells face upon their arrival in the lung. Are tumor cells seeded followed by being joined by 'helper'host cells or are successful mets captured directly by these cells? What are the kinetics of the proliferation of incoming metastatic cells relative to the recruitment of macrophages and bone-marrow derived cells? In what way is this process accelerated by ongoing damage repair? Better understanding of this, along with the development of a method to study it, will permit much more rational approaches toward blocking tumor metastasis.

Public Health Relevance

This proposal will apply novel intravital imaging of the lung to define the first hours following the arrival of metastatic cells into the mouse lung. As we know very little about why metastatic tumor cells survive in this environment, this represents a major undertaking in determining how to decrease their success.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA167601-02
Application #
8464682
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$157,938
Indirect Cost
$55,713
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143