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== Engineered Materials to Study Mechanisms of Stem Cell Motility in Metastasis ==
== Engineered Materials to Study Mechanisms of Stem Cell Motility in Metastasis ==


The overwhelming cause of morbidity in cancer patients is metastasis: the ability of tumor cells to mobilize, leave the primary tumor site, invade distant tissue, and launch secondary tumors.  In 1889, Dr. Steven Paget analyzed data from hundreds of breast cancer fatalities and noted that metastases were most often found in a specific subset of organs, e.g. the lung and liver.  Prior to this study, it was generally accepted that distant sites of metastasis were well-vascularized and had exceedingly narrow capillaries to physically trap circulating cells; however, Paget’s findings can not be explained by vascularization alone, and the physicochemical traits of certain organs and tissues that make them “predisposed” for metastasis remain unknown.  In addition to the primary site, the pre-metastatic niche is also an area of inflammation, and stem cells (mesenchymal, hematopoietic, and endothelial progenitors) are recruited to this distant site before the arrival of metastatic tumor cells.  These stem cells initiate the premetastatic niche by remodeling the local tissue microenvironment, altering matrix physicochemical properties, and attracting circulating tumor cells.   
The overwhelming cause of morbidity in cancer patients is metastasis: the ability of tumor cells to mobilize, leave the primary tumor site, invade distant tissue, and launch secondary tumors.  In 1889, Dr. Steven Paget analyzed data from hundreds of breast cancer fatalities and noted that metastases were most often found in a specific subset of organs, e.g. the lung and liver.  In addition to the primary site, the pre-metastatic niche is also an area of inflammation, and stem cells (mesenchymal, hematopoietic, and endothelial progenitors) are recruited to this distant site before the arrival of metastatic tumor cells.  These stem cells initiate the premetastatic niche by remodeling the local tissue microenvironment, altering matrix physicochemical properties, and attracting circulating tumor cells.  We are using engineered materials to study this metastatic cascade of events: stem cell-tumor cell crosstalk, stem cell mobilization and ensuing adhesion, proliferation, and remodeling of the pre-metastatic tissue, and the preferential attraction of circulating tumor cells.   
 
The goal of this proposal is to use engineered materials to study this metastatic cascade of events: stem cell-tumor cell crosstalk, stem cell mobilization and ensuing adhesion, proliferation, and remodeling of the pre-metastatic tissue, and the preferential attraction of circulating tumor cells.  To achieve this, I will design novel 2D matrices to mimic the natural in vivo niche occupied by quiescent stem cells, and engineer 3D synthetic materials with orthogonal control of enzymatic degradation, adhesivity, stiffness, and growth factor sequestering to regulate the adhesion, invasion, and matrix remodeling by stem cells.  Mechanistic approaches will test whether active proteolysis propels a positive feedback loop between matrix turnover and stem cell state, enhancing macrometastasis.  Completion of this proposal will catapult substantial progress in the field of cancer biology by revealing the physicochemical properties of materials and tissues that prime them for metastases.  My education and research training in Chemical Engineering, stem cell motility, and 3D tissue engineering has uniquely positioned me to tackle this question and meet the challenges of this ambitious and innovative research plan.


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Revision as of 08:46, 15 October 2010

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Engineered Materials to Study Mechanisms of Stem Cell Motility in Metastasis

The overwhelming cause of morbidity in cancer patients is metastasis: the ability of tumor cells to mobilize, leave the primary tumor site, invade distant tissue, and launch secondary tumors. In 1889, Dr. Steven Paget analyzed data from hundreds of breast cancer fatalities and noted that metastases were most often found in a specific subset of organs, e.g. the lung and liver. In addition to the primary site, the pre-metastatic niche is also an area of inflammation, and stem cells (mesenchymal, hematopoietic, and endothelial progenitors) are recruited to this distant site before the arrival of metastatic tumor cells. These stem cells initiate the premetastatic niche by remodeling the local tissue microenvironment, altering matrix physicochemical properties, and attracting circulating tumor cells. We are using engineered materials to study this metastatic cascade of events: stem cell-tumor cell crosstalk, stem cell mobilization and ensuing adhesion, proliferation, and remodeling of the pre-metastatic tissue, and the preferential attraction of circulating tumor cells.

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