A University of North Carolina Lineberger Comprehensive Cancer Center-led research team has used genetic insights about head and neck cancers linked to HPV, or human papillomavirus, to improve laboratory tools for studying the disease.
Leveraging their discovery that different subtypes of HPV-linked oropharyngeal squamous cell carcinoma exist based on the expression levels of two different viral genes, UNC Lineberger’s Antonio Amelio, PhD, and colleagues created a genetically engineered mouse model of HPV-linked oropharyngeal squamous cell carcinoma, a cancer of the back of the throat. Their findings on developing a model of HPV-linked head and neck cancer are published in Cell Reports.
“By creating a model of HPV-linked head and neck cancer that faithfully reflects the biology of the disease, we can use this to better understand the molecular mechanisms that cause this cancer,” said Amelio, who is an assistant professor in the UNC Adams School of Dentistry Division of Oral and Craniofacial Health Sciences and UNC Lineberger’s Cancer Cell Biology Program.
Amelio and his colleagues identified the two new subtypes based on how much of the viral genes E6 and E7 are expressed in infected cells. Amelio said the proteins encoded by the E6 and E7 genes remove certain checks and balances that are present in human cells to prevent unregulated growth.
Previous studies had verified the presence of E7, but the newly published research demonstrated that E6 is also present at similar levels. The gene helps to cause cancer by disrupting the function of the p53 tumor suppressor. Expression of both HPV genes is important to cause oropharyngeal cancer, the researchers found.
“We were puzzled by reports suggesting that E7 is the primary HPV gene expressed in these cancers. Gene expression analyses reveal significant changes in the p53 pathway, so we suspected that E6 must be expressed in infected cells,” Amelio said. “But other labs weren’t detecting it, which had to do with the computational methods that they were using to try and measure E6 expression.”
They discovered the two subtypes using data from a large genetic analysis of HPV-linked oropharyngeal cancer completed as part of a national project known as The Cancer Genome Atlas.
“What we found is these proteins are made at relatively equal levels, which is exactly what you would expect based on the downstream pathway dysregulation that you see in cancerous cells,” Amelio said.
The research team then created a mouse model of the predominant subtype of HPV-linked human oropharyngeal squamous cell carcinoma that reflects expression and anatomic locations of the HPV viral genes, and has an intact immune system.
“The lack of animal models has been one of the main challenges in making progress in this disease,” said D. Neil Hayes, MD, MPH, director of the Center for Cancer Research at the University of Tennessee Health Science Center, division chief of the UTHSC College of Medicine Division of Hematology-Oncology and Van Vleet Endowed Professor in Medical Oncology. “Now that we have this new tool, we are set to explore the disease and its treatment in a greatly accelerated manner.”
They plan to use their model to further understand the molecular mechanisms behind cancer’s development and progression in HPV-infected cells.
“Our model will allow researchers to define the genetic events that lead this virus to cause cancer in the head and neck and develop new targeted therapies,” Amelio said. “Using this model, we have already determined that a specific PIK3CA mutation represents a key driver mutation in this cancer type.”
In addition to Amelio, other authors included: Miranda B. Carpenter, Scott Troutman, Bethany L. Wagner, Kevin M. Byrd, Sara R. Selitsky, Kshitij P. Sharma, Erin C. Henry, Weimin Li, Joel S. Parker, Stephanie A. Montgomery, John L. Cleveland, Scott E. Williams, Joseph L. Kissil, and David N. Hayes.
The study was supported by the National Institute of Dental and Craniofacial Research, the National Cancer Institute, University of South Florida School of Medicine, the Dental Foundation of North Carolina, the University Cancer Research Fund, UNC Lineberger, and the NIH/NCI Howard Temin Pathway to Independence Award in Cancer Research.