Tumors must be able to induce angiogenesis in order to develop. Based on this mechanism, vascular-targeted therapies have been investigated in a variety of tumor types, with mixed results in clinical trials. Given the potential risks associated with these therapies, it is desirable to determine the characteristics of tissues (and hence, patients) that are most likely to respond to current inhibitors and identify additional therapeutic strategies. Angiogenesis occurs in a complex environment where endothelial cells are exposed to a variety of factors that are known to regulate angiogenesis, such as mechanical stiffness, extracellular matrix (ECM) density, and soluble growth factors. We hypothesize that the physical properties of the tumor microenvironment (e.g., stiffness, ECM density) impact tumor sensitivity to pro-angiogenic molecules, and therefore tumor responsiveness to vascular-targeted therapies.
Aim 1 : Evaluate how microenvironment properties impact endothelial cell (EC) responsiveness to soluble angiogenic stimuli. We will characterize the tumor microenvironment in a mouse model of breast cancer and apply this information to design a novel microfluidic-based culture system that enables independent variation of matrix stiffness and density. This system will be used to assess how different combinations of these characteristics impact cellular sensitivity to complex combinations of soluble angiogenic stimuli. We will then utilize computational modeling to analyze our experimental results in order to determine which angiogenic factors most strongly induce angiogenesis in the different physical microenvironments.
Aim 2 : Utilize tumor microenvironment properties and soluble factor combinations to predict EC responsiveness to vascular-targeted therapies. Using both our Aim 1 in vitro model and an in vivo mouse model of breast cancer, we will investigate whether the experimental and computational results gained in Aim 1 can be used to inform the selection of an optimal vascular-targeted strategies for a set microenvironment. By examining how the microenvironment regulates cellular sensitivity to angiogenic stimuli, this work aims to provide a foundation for predicting tumor responsiveness to vascular-targeted agents. The results obtained from these studies have the potential to inform the identification of treatment options for breast cancer.

Public Health Relevance

The formation of new blood vessels, known as angiogenesis, is a major contributing factor in the progression of numerous types of cancer. We propose to analyze how tumor angiogenesis is influenced by soluble biomolecules present at the tumor site and physical features of the tumor (e.g., stiffness, extracellular matrix density) in order to determine how changes in these properties impact vessel number, vessel quality, and sensitivity to vascular-targeted inhibitors. These studies will allow us to identify physical biomarkers of tissues that will respond to existing drugs as well as develop new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA202040-01
Application #
9015927
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kreeger, Pamela K; Strong, Laura E; Masters, Kristyn S (2018) Engineering Approaches to Study Cellular Decision Making. Annu Rev Biomed Eng 20:49-72
Bourgeois, Danielle L; Kreeger, Pamela K (2017) Partial Least Squares Regression Models for the Analysis of Kinase Signaling. Methods Mol Biol 1636:523-533
Masters, Kristyn S; Kreeger, Pamela K (2017) Ten simple rules for developing a mentor-mentee expectations document. PLoS Comput Biol 13:e1005709
Berger, Anthony J; Linsmeier, Kelsey M; Kreeger, Pamela K et al. (2017) Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen. Biomaterials 141:125-135