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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA143868-05
Application #
8548261
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,185,402
Indirect Cost
$851,694
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hielscher, Abigail; Gerecht, Sharon (2015) Hypoxia and free radicals: role in tumor progression and the use of engineering-based platforms to address these relationships. Free Radic Biol Med 79:281-91
Koride, Sarita; He, Li; Xiong, Li-Ping et al. (2014) Mechanochemical regulation of oscillatory follicle cell dynamics in the developing Drosophila egg chamber. Mol Biol Cell 25:3709-16
Aw Yong, Koh Meng; Zeng, Yu; Vindivich, Donald et al. (2014) Morphological effects on expression of growth differentiation factor 15 (GDF15), a marker of metastasis. J Cell Physiol 229:362-73
Capuano, Christopher M; Grzesik, Peter; Kreitler, Dale et al. (2014) A hydrophobic domain within the small capsid protein of Kaposi's sarcoma-associated herpesvirus is required for assembly. J Gen Virol 95:1755-69
Wang, Pu; Guan, Pei-Pei; Wang, Tao et al. (2014) Interleukin-1? and cyclic AMP mediate the invasion of sheared chondrosarcoma cells via a matrix metalloproteinase-1-dependent mechanism. Biochim Biophys Acta 1843:923-33
Stroka, Kimberly M; Konstantopoulos, Konstantinos (2014) Physical biology in cancer. 4. Physical cues guide tumor cell adhesion and migration. Am J Physiol Cell Physiol 306:C98-C109
Li, Bo; Sun, Sean X (2014) Coherent motions in confluent cell monolayer sheets. Biophys J 107:1532-41
Stroka, Kimberly M; Jiang, Hongyuan; Chen, Shih-Hsun et al. (2014) Water permeation drives tumor cell migration in confined microenvironments. Cell 157:611-23
Wang, Ting; Gilkes, Daniele M; Takano, Naoharu et al. (2014) Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 111:E3234-42
Park, Kyung Min; Gerecht, Sharon (2014) Hypoxia-inducible hydrogels. Nat Commun 5:4075

Showing the most recent 10 out of 104 publications