The goal of our studies is to develop a quantitative understanding of tumor metastasis. As cell migration is the central part of metastasis, we are developing quantitative experimental and computational methods to study migration in three dimensional matrices. Our preliminary studies have indicated that cancer cell migration in two and three dimensional matrices is significantly different. The effects of matrix structure and mechanics as well as extracellular degradation by proteolytic enzymes can not be studied in existing two dimensional assays. This lack of information about key processes and variables leads to incomplete and inaccurate understanding. Our goal is to rectify these problems by quantifying tumor cell migration in native like three dimensional environments. In the proposed studies, we will develop a system level understanding of tumor cell migration. The individual and collective roles of cell adhesion, matrix composition, matrix structure and proteolysis will be studied in well established prostate cancer cell lines. This will be accomplished through the following specific aims: 1) Quantify the systematic interactions of integrins and extracellular matrix in regulating three -dimensional tumor cell motility, 2) Quantify the effects of extracellular matrix structure on protease activity in tumor cells and 3) Develop multi-scale computational models to predict and quantify cell adhesion and migration in three dimensional matrices. Our ability to combat and cure cancer rests on our understanding of the processes regulating metastasis. The project outlined in this proposal will be a significant step in reaching that level of understanding. By combining experiments and simulations, carried out in controlled environments that mimic in vivo settings, we will be able to quantify the individual and collective roles of matrix and cells in tumor cell migration. The systems level quantification achieved through our experiments and simulation will serve as a platform for discovery of anti- cancer therapeutics. Principal Investigator/Program Director (Last, first, middle): Zaman, Muhammad H., Ph.D..

Public Health Relevance

The main reason for cancer related deaths is the progression of cancer from a localized tumor to the vital organs of the body, a process otherwise known as metastasis. Thus our ability to combat and cure cancer rests on our understanding of the processes regulating metastasis. The project outlined in this proposal will be a significant step in reaching that level of understanding. Page 5

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132633-05
Application #
8131688
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Couch, Jennifer A
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$279,334
Indirect Cost
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Singh, S P; Schwartz, M P; Tokuda, E Y et al. (2015) A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression. Sci Rep 5:17814
Leight, Jennifer L; Tokuda, Emi Y; Jones, Caitlin E et al. (2015) Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition. Proc Natl Acad Sci U S A 112:5366-71
Sakamoto, Y; Prudhomme, S; Zaman, M H (2014) Modeling of adhesion, protrusion, and contraction coordination for cell migration simulations. J Math Biol 68:267-302
Tokuda, Emi Y; Leight, Jennifer L; Anseth, Kristi S (2014) Modulation of matrix elasticity with PEG hydrogels to study melanoma drug responsiveness. Biomaterials 35:4310-8
Vargas, Diego A; Bates, Oliver; Zaman, Muhammad H (2013) Computational model to probe cellular mechanics during epithelial-mesenchymal transition. Cells Tissues Organs 197:435-44
Chisholm, Rebecca H; Hughes, Barry D; Landman, Kerry A et al. (2013) Analytic study of three-dimensional single cell migration with and without proteolytic enzymes. Cell Mol Bioeng 6:
Harjanto, Dewi; Zaman, Muhammad H (2013) Modeling extracellular matrix reorganization in 3D environments. PLoS One 8:e52509
Katira, Parag; Zaman, Muhammad H; Bonnecaze, Roger T (2012) How changes in cell mechanical properties induce cancerous behavior. Phys Rev Lett 108:028103
Lepzelter, David; Zaman, Muhammad (2012) Subdiffusion of proteins and oligomers on membranes. J Chem Phys 137:175102
Lepzelter, David; Bates, Oliver; Zaman, Muhammad (2012) Integrin clustering in two and three dimensions. Langmuir 28:5379-86

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