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

doi:10.1016/j.celrep.2019.10.005

An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma

Cell Rep. 2019 Nov 5;29(6):1660-1674.e7. doi: 10.1016/j.celrep.2019.10.005.

Authors

Affiliations

¹ Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
³ 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.
⁴ 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.
⁵ Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ 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.
⁷ Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
⁹ 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.
¹⁰ Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ 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.
¹² 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.
¹³ 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. Electronic address: [email protected].

Abstract

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 PIK3CA^E545K 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.

Keywords: GEMM, human papilloma virus; HNSCC; HPV; HPV16; LumiFluor; OPSCC; genetically engineered mouse model; head and neck squamous cell carcinoma; immunocompetent; oncogene; oropharyngeal squamous cell carcinoma; tumor suppressor; tumorigenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases / genetics
Class I Phosphatidylinositol 3-Kinases / metabolism
Disease Models, Animal*
Female
Gene Expression
Head and Neck Neoplasms / genetics
Head and Neck Neoplasms / immunology
Head and Neck Neoplasms / metabolism
Head and Neck Neoplasms / virology*
Humans
Immunocompetence
Internal Ribosome Entry Sites / genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Natural Killer T-Cells / immunology
Natural Killer T-Cells / metabolism
Oncogene Proteins, Viral / genetics
Oncogene Proteins, Viral / metabolism*
Oropharyngeal Neoplasms / genetics
Oropharyngeal Neoplasms / immunology
Oropharyngeal Neoplasms / metabolism
Oropharyngeal Neoplasms / virology*
Papillomavirus E7 Proteins / genetics
Papillomavirus E7 Proteins / metabolism*
RNA Splicing / genetics
RNA-Seq
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Squamous Cell Carcinoma of Head and Neck / genetics
Squamous Cell Carcinoma of Head and Neck / immunology
Squamous Cell Carcinoma of Head and Neck / metabolism
Squamous Cell Carcinoma of Head and Neck / virology*
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism

Substances

E6 protein, Human papillomavirus type 16
Internal Ribosome Entry Sites
Oncogene Proteins, Viral
Papillomavirus E7 Proteins
Repressor Proteins
oncogene protein E7, Human papillomavirus type 16
Class I Phosphatidylinositol 3-Kinases
Pik3ca protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding