An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma
Miranda B. Carper,
Scott Troutman,
Bethany L. Wagner,
Kevin M. Byrd,
Sara R. Selitsky,
Kshitij Parag-Sharma,
Erin C. Henry,
Weimin Li,
Joel S. Parker,
Stephanie A. Montgomery,
John L. Cleveland,
Scott E. Williams,
Joseph L. Kissil,
David N. Hayes,
Antonio L. Amelio
Affiliations
Miranda B. Carper
Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Scott Troutman
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
Bethany L. Wagner
Graduate Curriculum in Pathobiology and Translational Medicine, Biological & Biomedical Sciences Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Kevin M. Byrd
Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Graduate Curriculum in Oral & Craniofacial Biomedicine, Biological & Biomedical Sciences Program, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Sara R. Selitsky
Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Kshitij Parag-Sharma
Graduate Curriculum in Cell Biology and Physiology, Biological & Biomedical Sciences Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Erin C. Henry
Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Weimin Li
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
Joel S. Parker
Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Stephanie A. Montgomery
Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
John L. Cleveland
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
Scott E. Williams
Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Joseph L. Kissil
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
David N. Hayes
Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medical Oncology, University of Tennessee Health Sciences West Cancer Center, Memphis, TN, USA
Antonio L. Amelio
Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Biomedical Research Imaging Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding author
Summary: The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression. : Carper et al. present the “iKHP” mouse, in which HPV16 oncogenes are inducibly activated in vivo in a tissue-specific and temporal manner. Oropharyngeal-specific expression of E6/E7 with PIK3CAE545K in these mice promotes the development of premalignant lesions marked by immune cell infiltration, but only a subset spontaneously convert to OPSCC. Keywords: genetically engineered mouse model, GEMM, human papilloma virus, HPV, HPV16, head and neck squamous cell carcinoma, HNSCC, oropharyngeal squamous cell carcinoma, OPSCC, immunocompetent, tumorigenesis, oncogene, tumor suppressor, LumiFluor
