Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

Abstract

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis.

CD244 represents a new therapeutic target in head and neck squamous cell carcinoma

“…For these experiments, we use fresh biopsy samples from human (HNSCC) patients and a syngeneic mouse model of HNSCC (MEER). 41 We demonstrate that CD244 expression increases in intratumoral CD8 + T cells, MHC II + CD11c + DCs and monocytic MDSCs (Mo-MDSCs) compared with peripheral counterparts, and correlates with PD-1 or PD-L1 expression. In addition, increased CD244 expression corresponds to increases in molecules associated with immunosuppressive function in human and mouse intratumoral immune cells.…”

Mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV‐related head and neck cancer

“…While the preclinical value of the parental and related cell lines has so far only been explored in the flank mouse model, 26,27 our approach is the first to successfully integrate implantation of these cells into the submental FOM region with surgery. While the preclinical value of the parental and related cell lines has so far only been explored in the flank mouse model, 26,27 our approach is the first to successfully integrate implantation of these cells into the submental FOM region with surgery.…”

“…In the present work, we report on the development of a mouse model designed to study postsurgical local recurrence derived from MRD and ECS of LNMs. While the preclinical value of the parental and related cell lines has so far only been explored in the flank mouse model, 26,27 our approach is the first to successfully integrate implantation of these cells into the submental FOM region with surgery. In this way, we could mimic such clinical cases managed by surgery as a primary treatment.…”

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

“…In addition, our tumor model is non-metastatic (Vermeer et al, 2016; Vichaya et al, 2016). Many of the previous findings of tumor-induced neuroinflammation were obtained in model systems that are highly cachectic (Braun et al, 2011; Norden et al, 2015; Ropelle et al, 2007).…”