Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis
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Daniel W. Vermeer1, Joseph D. Coppock1, Erliang Zeng2,3, Kimberly M. Lee1, William C. Spanos1,4, Michael D. Onken5, Ravindra Uppaluri6, John H. Lee1,4, Paola D. Vermeer1
1Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA
2Department of Biology, University of South Dakota, Vermillion, South Dakota, USA
3Department of Computer Science, University of South Dakota, Vermillion, South Dakota, USA
4Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, South Dakota, USA
5Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
6Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA
Paola D. Vermeer, e-mail: Paola.Vermeer@SanfordHealth.org
Keywords: head and neck oral cancer, human papillomavirus, metastasis, recurrence
Received: October 19, 2015 Accepted: March 06, 2016 Published: March 22, 2016
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.
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