Metastatic disease remains the primary cause of death for patients with most types of cancer. Metastasis occurs through a series of interrelated steps, including survival of cancer cells in the circulation, adhesion to endothelial cells lining blood vessels, and growth of cancer cells to form metastases. Successfully interrupting any one of these steps will stop metastatic disease and potentially cure cancer. Research on metastasis has focused on primary tumors and organs with established metastases. Very little is known about cancer cells in the vascular system, an environment where mechanical forces and molecular interactions between malignant cells and vascular endothelium control the fate of circulating tumor cells. The intravascular microenvironment in metastasis is a fertile research area ripe for new therapeutic strategies to block this fatal step in cancer. What is required, however, is an efficient method for investigating the vascular microenvironment under physiologic, yet efficient and systematically adjustable conditions. To meet this critical need in cancer research, we have developed a microfluidic device to model key physical, molecular, and cellular components of the intravascular microenvironment in metastasis. We will use this device to test two central hypotheses: 1) chemokine receptor CXCR4 and the newly identified chemokine receptor CXCR7 have additive or synergistic effects to promote intravascular steps in metastasis;and 2) endothelial molecules including CXCR4 and CXCR7 control tissue-specific metastatic potential of circulating breast cancer cells.
In Aim 1, we will engineer a microfluidic flow device to reproduce mechanical stresses of the vasculature and generate spatially- restricted gradients of chemoattractant molecules.
In Aim 2, we will use the microfluidic flow system to investigate integrated functions of CXCR4 and CXCR7 on breast cancer cells in responding to the pro- metastatic chemokine CXCL12.
Aim 3 will investigate endothelial-specific regulation of cancer cell adhesion and proliferation, exploiting our capabilities to integrate multiple types of endothelium into one flow system and then rapidly recover cells for analysis. Endothelial regulators of metastasis are particularly appealing therapeutic targets because these cells are less likely to develop drug resistance. Collectively, this research will develop innovative microfluidic flow models to study intravascular steps in metastasis under physiologic conditions, allowing us to identify breast cancer and endothelial molecules that can be targeted therapeutically to prevent metastatic disease.

Public Health Relevance

This research will develop new, physiologic cell culture models of blood vessels to study interactions between circulating breast cancer cells and vascular endothelium during metastasis. These models should greatly advance our knowledge of metastatic disease and enable more rapid testing and validation of new cancer therapeutics to treat or prevent metastatic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136829-04
Application #
8215885
Study Section
Instrumentation and Systems Development Study Section (ISD)
Program Officer
Snyderwine, Elizabeth G
Project Start
2009-04-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$304,106
Indirect Cost
$102,831
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Coggins, Nathaniel L; Trakimas, Danielle; Chang, S Laura et al. (2014) CXCR7 controls competition for recruitment of ?-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS One 9:e98328
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Zhao, Shuang; Chang, S Laura; Linderman, Jennifer J et al. (2014) A Comprehensive Analysis of CXCL12 Isoforms in Breast Cancer(1,2.) Transl Oncol :
Luker, Kathryn E; Luker, Gary D (2014) Split Gaussia luciferase for imaging ligand-receptor binding. Methods Mol Biol 1098:59-69
Cavnar, S P; Ray, P; Moudgil, P et al. (2014) Microfluidic source-sink model reveals effects of biophysically distinct CXCL12 isoforms in breast cancer chemotaxis. Integr Biol (Camb) 6:564-76
Moraes, Christopher; Simon, Arlyne B; Putnam, Andrew J et al. (2013) Aqueous two-phase printing of cell-containing contractile collagen microgels. Biomaterials 34:9623-31
Toubai, Tomomi; Sun, Yaping; Luker, Gary et al. (2013) Host-derived CD8+ dendritic cells are required for induction of optimal graft-versus-tumor responses after experimental allogeneic bone marrow transplantation. Blood 121:4231-41
Ehrlich, Anna; Ray, Paramita; Luker, Kathryn E et al. (2013) Allosteric peptide regulators of chemokine receptors CXCR4 and CXCR7. Biochem Pharmacol 86:1263-71

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