Many human cancers contain regions of hypoxia, resulting in cell death and establishing a selection for cancer cells. Cancer cells adapt to the hypoxic microenvironment is through the activity of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 also plays a critical role in tumor vascularization by activation of endothelial progenitors and cells. Project 1 will investigate the functional interactions between HIF-1 and extracellular matrix (ECM), both in cancer cells and in endothelial progenitors and cells. This is a unique perspective that takes into account how one aspect of the tumor microenvironment (02 concentration) regulates and interacts with another (mechanical properties of the ECM) to alter the cancer cell phenotype. The combined utilization of biophysical, biochemical, biological, computational, and engineering approaches that we propose will provide new insights into the mechanisms underlying metastasis.
The Specific Aims are: (1) To determine whether alterations in mechanical properties of the ECM alter the phenotype of cancer cells.(2) To determine whether hypoxia and/or increased HIF-1 activity induces changes in mechanical properties of the ECM, which in turn alter the phenotype of cancer cells. (3) To determine whether alterations in mechanical properties of the ECM regulate HIF-1 activity, leading to alterations in cancer cell phenotype. (4) To determine whether changes in ECM mechanical properties alter the phenotype of endothelial progenitors and cells. (5) To determine whether HIF-1-induced changes in ECM mechanical properties alter the phenotype of endothelial progenitors and cells. Linkage to PS-OC:
The research aims of Project 1 fit the overarching theme of the Center of the cooperative role of HIF-1 and EMC in the metastatic cascade;
Aims 1 and 2 are synergistically connected to Aims 1-4 in Project 2 and Aims 1 and 2 in Project 3 for further research integration of the Center;all Students and Fellows in the Project will be enrolled in the Center Training Program;this project will make use of the resources provided by the Imaging Core, as well as the Administrative Unit of the Center;cell lines and micromechanical methods will be the same as those used in all projects;computational efforts will be shared among all projects.
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