Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, and there has been only a limited increase in survival rate over the last 30 years unlike the significant survival improvements in better-studied cancer types such as breast and prostate. Although molecular alterations are overall poorly characterized in HNSCC, the actin-binding protein cortactin has been shown to be overexpressed in 30-40% of HNSCC, due to the presence of its gene (CTTN) in the 11q13 amplicon. Importantly, numerous studies have shown that cortactin overexpression at the protein, mRNA and genomic DNA levels is highly correlated with poor prognosis. Cortactin was originally identified as a src kinase substrate, and has been shown to be important in actin cytoskeleton rearrangement, migration, and invasion. Our laboratory has shown cortactin to be important for various cancer-associated phenotypes in HNSCC, including tumor growth and invasion, serum- and anchorage-independent growth, migration and invadopodia formation. Our recent data suggest that underlying mechanisms for these phenotypes include alterations in membrane trafficking, with consequent regulation in secretion of proteinases and other autocrine secreted factors. Cortactin binds to a number of proteins necessary for cancer progression, including Src kinase and filamentous actin (F-actin). However, the molecular mechanisms and cortactin-binding proteins that are important for these functions of cortactin have yet to be elucidated. To determine the molecular interactions of cortactin that are important in promoting tumor aggression, I propose two specific aims: 1, to determine which cortactin binding interactions are critical for cortactin-dependent HNSCC cell phenotypes in vitro and in vivo;and 2, to test the role of cortactin binding partners in cortactin-sensitive cellular phenotypes. By investigating these aims, I hope to identify new potential therapeutic targets for treatment of HNSCC.

Public Health Relevance

The actin binding gene cortactin is overexpressed in 30-40% of head and neck squamous cell carcinoma, and generally correlates with poor prognosis and more aggressive cases. However, the molecular mechanisms by which cortactin promotes aggressiveness are poorly understood. This proposal seeks to elucidate which cortactin binding partners and domains are critical for tumor cell phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DE021619-04
Application #
8528393
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2010-09-03
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$36,632
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212