Animal Models to Study the Mutational Landscape for Oral Cavity and Oropharyngeal Cancers

Abstract

ObjectivesCancer is likely caused by alterations in gene structure or expression. Recently, next generation sequencing has documented mutations in 106 head and neck squamous cell cancer genomes, suggesting several new candidate genes. However, it remains difficult to determine which mutations directly contributed to cancer. Here, summarize the animal models which have already validated and may test cancer causing mutations identified by next generation sequencing approaches.Material and MethodsWe reviewed the existing literature on genetically engineered mouse models and next generation sequencing (NGS), as it relates to animal models of squamous cell cancers of the head and neck (HNSCC) in PubMed.ResultsNSG has identified an average of 19 to 130 distinct mutations per HNSCC specimen. While many mutations likely had biological significance, it remains unclear which mutations were essential to, or "drive," carcinogenesis. In contrast, "passenger" mutations also exist that provide no selection advantage. The genes identified by NGS included p53, RAS, Human Papillomavirus oncogenes, as well as novel genes such as NOTCH1, DICER and SYNE1,2. Animal models of HNSCC have already validated some of these common gene mutations identified by NGS.Conclusions The advent of next generation sequencing will provide new leads to the genetic changes occurring in squamous cell cancers of the head and neck. Animal models will enable us to validate these new leads in order to better elucidate the biology of squamous cell cancers of the head and neck.

Cell-Free DNA Kinetics in a Pre-Clinical Model of Head and Neck Cancer

“…There are currently few suitable pre-clinical animal models for HPV-related HNSCC 25 , and plasma HPV DNA kinetics in animal models have not been reported. Here, we examine ctDNA kinetics in an orthotopic, immunocompetent rabbit model of papillomavirus-associated squamous cell carcinoma.…”

RNAi-Mediated Knockdown of Cottontail Rabbit Papillomavirus Oncogenes Using Low-Toxicity Lipopolyplexes as a Paradigm to Treat Papillomavirus-Associated Cancers

“…CRPV, like HPV, induces papillomatosis, possibly leading to the development of squamous cell carcinomas. The metastatic pattern of VX2 tumors mimics the natural pattern seen in HPV-associated human HNSCC [10]. In this context, the VX2 model helps us to better understand HPV-associated tumors.…”

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

“…Several in vitro and in vivo model systems exist for investigating HPV-associated pathogenesis (Doorbar, 2016; Lambert, 2016; Spiotto et al, 2013), but the currently available GEMMs each have a unique set of limitations that must be considered when designing studies (Table S4). These HPV GEMM models fall into two broad categories, namely, those that display constitutive versus those with inducible HPV16 E6 and/or E7 oncogene expression.…”

“…However, the spontaneous and incomplete conversion of all pre-malignant lesions to HNSCC also presents an intriguing opportunity to evaluate the utility of this model for investigating those molecular events responsible for the progression of only a subset of lesions to malignancy. Although previous models of oral tumorigenesis expressed CCND1 , mutant Kras , Tp53 , Tgfbr1 , or Notch1 (Spiotto et al, 2013), we specifically chose to investigate the contribution of mutant PIK3CA in promoting the development of HNSCCs given accumulating genomic sequencing evidence pointing to a potential role for PIK3CA amplification and/or mutation as a key driver event (Gillison et al, 2018; Hayes et al, 2015; Leemans et al, 2018; Cancer Genome Atlas Network, 2015). Aberrant PI3K signaling enhances tumorigenic potential by increasing cell proliferation and survival and promoting migration, invasion, metabolism, angiogenesis, as well as resistance to chemotherapy (Hafsi et al, 2012; Wong et al, 2010; Yuan and Cantley, 2008).…”