Understanding the mechanism that promotes invasion and spread of head and neck cancer (SCCHN) will provide novel mechanism-based strategies to treat this disease. Patients with SCCHN often develop resistance to treatment, which leads to tumor recurrence. Consequently, almost half of SCCHN patients die within five years of diagnosis. Despite this dismal outlook, there have been no novel treatments in over forty years, underscoring the need for new treatment strategies. Understanding the molecular mechanisms regulating head and neck cancers is essential for effective treatment. Tumor-initiating or stem cells, and invasive cells repopulate the tumor and spread to distant sites after "successful" treatment. Since cellular plasticity required for invasion, recurrence and spread is primarily regulated epigenetically, treatment strategies that target the epigenetic mechanism are important. The proposed study focuses on a major epigenetic regulatory mechanism that integrates invasion, and stemness-mediated treatment resistance via epithelial-to- mesenchymal transition (EMT). The central hypothesis is that EZH2 promotes SCCHN progression and recurrence by inducing rap1/EMT-mediated invasion and stemness;this critical role makes EZH2 an excellent treatment target. We will test our hypothesis by pursuing the following aims: #1) To investigate the mechanism by which EZH2 promotes invasion in SCCHN;#2) To define the mechanism of EZH2-induced treatment resistance;and #3) To evaluate the clinical relevance of EZH2 expression in human tissue. We will accomplish the objectives of this application using cell lines, 2D and novel 3D in vitro models, newly developed in vivo models of human SCCHN, and human tissue. The proposed studies will identify novel mechanisms through which rap1 integrates epigenetic reprogramming and EMT-mediated invasion, stemness and treatment resistance in SCCHN. Thus, our findings will facilitate the design of rational strategies to treat SCCHN.

Public Health Relevance

Head and neck cancer is the sixth most common cancer globally. Despite intense therapy and rehabilitation, about half of the patients die in less than five years after diagnosis. At 600,000 new cases a year, this is a tremendous loss of life. Thus, understanding the mechanisms that regulate the aggressive features of head and neck cancer, including invasion and spread, is essential for the development of new mechanism-based treatment. Since cellular plasticity required for invasion and spread is primarily regulated epigenetically, treatment strategies that target the epigenetic mechanism are important. The proposed study focuses on a major epigenetic regulatory mechanism that promotes invasion and treatment resistance. This research can impact national and global health by diminishing mortality, improving quality of life and reducing treatment costs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022567-01A1
Application #
8576552
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Venkatachalam, Sundaresan
Project Start
2013-09-26
Project End
2017-07-31
Budget Start
2013-09-26
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$349,875
Indirect Cost
$124,875
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Inglehart, Ronald C; Scanlon, Christina S; D'Silva, Nisha J (2014) Reviewing and reconsidering invasion assays in head and neck cancer. Oral Oncol 50:1137-43
Banerjee, Rajat; Van Tubergen, Elizabeth A; Scanlon, Christina S et al. (2014) The G protein-coupled receptor GALR2 promotes angiogenesis in head and neck cancer. Mol Cancer Ther 13:1323-33
Banerjee, Rajat; Russo, Nickole; Liu, Min et al. (2014) TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nat Commun 5:4527