The insulin-like growth factor 1 receptor (IGF1 R) is an essential regulator of cell growth and transformation, that promotes tumor cell proliferation, motility and protection from apoptosis. We have shown that in oral squamous cell carcinoma (OSCC) cells IGF1 R activation increases vascular endothelial growth factor (VEGF) synthesis and secretion, initiating an autocrine VEGF:VEGFR2 signaling loop. Our overall hypothesis stipulates that VEGF signaling via VEGFR2, leads to enhanced OSCC tumorigenicity and invasive cell behavior. In strong support of this hypothesis we have used a phosphotyrosine proteomics screen and identified a cluster of proteins involved in cell motility that is activated by VEGF stimulation. These proteins include human enhancer of filamentationi (HEF1), cortactin, paxillin, and focal adhesion kinase. Of significance, HEFI has been identified as a signature protein required for metastasis in melanoma, glioblastoma and breast cancer. The goal of AIM I is to define the mechanism through which HEF1 mediates VEGF induced OSCC cell migration and invasion. To this end, we will define the specific tyrosine residues in HEF1 that are phosphorylated in response to VEGFR2 activation using complementary biochemical techniques and site-directed mutagenesis.
In AIM 2 we will define VEGF regulation of invadopodia formation and the structural and functional contributions of HEFI to this process. As a subset of this aim we will examine HEFI localization to invadopodia and what domains on HEF1 enable its association with invadopodia. These studies should provide important evidence demonstrating a role for HEFI in OSCC metastatic signaling downstream of crosstalk to VEGFR2. They will lead to the development of novel strategies and therapeutic agents aimed at reducing the tumorigenic and metastatic effects of the IGF and VEGF pathways in OSCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA134845-01A1
Application #
7654748
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$224,569
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Grauzam, Stéphane; Brock, Amanda M; Holmes, Casey O et al. (2018) NEDD9 stimulated MMP9 secretion is required for invadopodia formation in oral squamous cell carcinoma. Oncotarget 9:25503-25516
Rosenzweig, Steven A (2018) Acquired Resistance to Drugs Targeting Tyrosine Kinases. Adv Cancer Res 138:71-98
Coaxum, Sonya D; Tiedeken, Jessica; Garrett-Mayer, Elizabeth et al. (2017) The tumor suppressor capability of p53 is dependent on non-muscle myosin IIA function in head and neck cancer. Oncotarget 8:22991-23007
Jezierska-Drutel, Agnieszka; Rosenzweig, Steven A; Neumann, Carola A (2013) Role of oxidative stress and the microenvironment in breast cancer development and progression. Adv Cancer Res 119:107-25
Rossa Jr, Carlos; Sommer, Gunhild; Spolidorio, Luis C et al. (2012) Loss of expression and function of SOCS3 is an early event in HNSCC: altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. PLoS One 7:e45197
Rosenzweig, Steven A (2012) Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem Pharmacol 83:1041-8
Swain, Monalisa; Slomiany, Mark G; Rosenzweig, Steven A et al. (2010) High-yield bacterial expression and structural characterization of recombinant human insulin-like growth factor binding protein-2. Arch Biochem Biophys 501:195-200
Mulligan, Jennifer K; Rosenzweig, Steven A; Young, M Rita I (2010) Tumor secretion of VEGF induces endothelial cells to suppress T cell functions through the production of PGE2. J Immunother 33:126-35
Lucas Jr, J T; Salimath, B P; Slomiany, M G et al. (2010) Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent. Oncogene 29:4449-59
Rosenzweig, Steven A; Atreya, Hanudatta S (2010) Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem Pharmacol 80:1115-24

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